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References 4 website: JMR, http://fluoroquinolonethyroid.com
References 4
Links, Abstracts, Articles, etc.
These links should work as of 2014; sometimes you have to click
on them
several times; if they don’t work, then Google/search the
titles
Thyroid Hormones and Mitochondria abstracts The mitochondrion as
a primary site of action of steroid and thyroid hormones: presence
and action of steroid and thyroid hormone receptors in mitochondria
of animal cells.
Authors
Psarra AM, Solakidi S, Sekeris CE
Source
Molecular and cellular endocrinology 246:1-2 2006 Feb 26 pg
21-33
Abstract
Mitochondria are key cellular organelles that regulate events
related to energy production and apoptosis. These processes are
modulated, in turn, by steroid and thyroid hormones in the course
of their actions on metabolism, growth and development. In this
context, a direct effect of these hormones on the
mitochondrial-linked processes, possibly by way of cognate
mitochondrial receptors, has been proposed. In this paper we review
data from the literature and present new findings supporting this
concept. Receptors for steroid hormones, glucocorticoids and
estrogens, and for T(3), have been detected in mitochondria by
immunofluorescence labeling and confocal laser microscopy, by
Western blotting of mitochondrial proteins and by immunogold
electron microscopy. Furthermore, the mitochondrial genome contains
nucleotide sequences with high similarity to known
hormone-responsive elements, which interact with the appropriate
receptors to confer hormone-dependent activation of reporter genes
in transfection experiments. Thus, thyroid hormone stimulates
mitochondrial transcription mediated by the cognate receptor when
added to an in organello mitochondrial system, capable of faithful
transcription.
Mitochondrial genes as sites of primary action of steroid
hormones.
Authors
Demonacos CV, Karayanni N, Hatzoglou E, Tsiriyiotis C, Spandidos
DA, Sekeris CE
Source
Steroids 61:4 1996 Apr pg 226-32
http://www.unboundmedicine.com/medline/?st=M&author=Demonacos%20CVhttp://www.unboundmedicine.com/medline/?st=M&author=Karayanni%20Nhttp://www.unboundmedicine.com/medline/?st=M&author=Hatzoglou%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Tsiriyiotis%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Spandidos%20DAhttp://www.unboundmedicine.com/medline/?st=M&author=Sekeris%20CEhttp://www.unboundmedicine.com/medline/?st=M&journal=Steroids
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Abstract
Steroid and thyroid hormones act on nuclear gene transcription
by activating protein receptors, which in turn bind to hormone
response elements (HREs). Among these cell-specific processes
regulated by steroid receptors is energy metabolism through
increased synthesis of respiratory enzymes. As some of these
enzymes are encoded by both nuclear and mitochondrial genes,
coordination of their synthesis is probable, inter alia at the
transcriptional level. We have postulated a direct effect of
steroid hormones on mitochondrial gene transcription and here
present the following evidence in support of this hypothesis. 1)
The human and rodent mitochondrial genomes contain nucleotide
sequences similar both to type I and type II HREs. 2)
Glucocorticoid receptors (GR) rapidly translocate from the
cytoplasm into mitochondria after administration of
glucocorticoids. This process has been reproduced in vitro and
deletion of the N-terminal part of the glucocorticoid receptor
stops translocation into mitochondria. 3) Gel shift analysis has
demonstrated binding of GR to putative mitochondrial GR elements.
4) In transfection experiments, mitochondrial HREs confer
dexamethasone inducibility on hybrid reporter constructs, abolished
in the presence of excess RU38486. 5) Similar results were obtained
for thyroid hormone receptor (TR alpha) localization, import, and
binding to TR elements. These findings, taken with the demonstrated
effects of steroid (and thyroid) hormones on mitochondrial
transcription and respiratory enzyme biosynthesis, strongly support
the hypothesis of a direct effect of steroid (and thyroid) hormones
on mitochondrial gene transcription.
Glucocorticoid and thyroid hormone receptors in mitochondria of
animal cells.
Authors
Scheller K, Seibel P, Sekeris CE
Source
International review of cytology 222: 2003 pg 1-61
Abstract
This article concerns the localization of glucocorticoid and
thyroid hormone receptors in mitochondria of animal cells. The
receptors are discussed in terms of their potential role in the
regulation of mitochondrial transcription and energy production by
the oxidative phosphorylation pathway, realized both by
nuclear-encoded and mitochondrially encoded enzymes. A brief survey
of the role of glucocorticoid and thyroid hormones on energy
metabolism is presented, followed by a description of the molecular
mode of action of these hormones and of the central role of the
receptors in regulation of transcription. Subsequently, the
structure and characteristics of glucocorticoid and thyroid hormone
receptors are described, followed by a section on the effects of
glucocorticoid and thyroid hormones on the transcription of
mitochondrial and nuclear genes encoding subunits of OXPHOS and by
an introduction to the mitochondrial genome and its transcription.
A comprehensive description of the data demonstrates the
localization of glucocorticoid and thyroid hormone receptors in
mitochondria as well as the detection of potential hormone response
elements that bind to these receptors. This leads to the conclusion
that the receptors potentially play a role in the regulation of
transcription of mitochondrial genes. The in organello
mitochondrial system, which is capable of sustaining transcription
in the absence of nuclear participation, is presented, responding
to T3 with increased transcription rates, and the central role of a
thyroid receptor isoform in the transcription effect is emphasized.
Lastly, possible ways of coordinating nuclear and mitochondrial
gene transcription in response to glucocorticoid and thyroid
hormones are discussed, the hormones acting directly on the genes
of the two compartments by way of common hormone response elements
and indirectly on mitochondrial genes by stimulation of
nuclear-encoded transcription factors.
http://www.unboundmedicine.com/medline/?st=M&author=Scheller%20Khttp://www.unboundmedicine.com/medline/?st=M&author=Seibel%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Sekeris%20CEhttp://www.unboundmedicine.com/medline/?st=M&journal=Int%20Rev%20Cytol
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Thyroid hormone action in mitochondria.
Authors
Wrutniak-Cabello C, Casas F, Cabello G
Source
Journal of molecular endocrinology 26:1 2001 Feb pg 67-77
Abstract
Triiodothyronine (T3) is considered a major regulator of
mitochondrial activity. In this review, we show evidence of the
existence of a direct T3 mitochondrial pathway, and try to clarify
the respective importance of the nuclear and mitochondrial pathways
for organelle activity. Numerous studies have reported short-term
and delayed T3 stimulation of mitochondrial oxygen consumption.
Convincing data indicate that an early influence occurs through an
extra-nuclear mechanism insensitive to inhibitors of protein
synthesis. Although it has been shown that diiodothyronines could
actually be T3 mediators of this short-term influence, the
detection of specific T3-binding sites, probably corresponding to a
28 kDa c-Erb Aalpha1 protein of the inner membrane, also supports a
direct T3 influence. The more delayed influence of thyroid hormone
upon mitochondrial respiration probably results from mechanisms
elicited at the nuclear level, including changes in phospholipid
turnover and stimulation of uncoupling protein expression, leading
to an increased inner membrane proton leak. However, the
involvement of a direct mitochondrial T3 pathway leading to a rapid
stimulation of mitochondrial protein synthesis has to be
considered. Both pathways are obviously involved in the T3
stimulation of mitochondrial genome transcription. First, a 43 kDa
c-Erb Aalpha1 protein located in the mitochondrial matrix (p43),
acting as a potent T3-dependent transcription factor of the
mitochondrial genome, induces early stimulation of organelle
transcription. In addition, T3 increases mitochondrial TFA
expression, a mitochondrial transcription factor encoded by a
nuclear gene. Similarly, the stimulation of mitochondriogenesis by
thyroid hormone probably involves both pathways. In particular, the
c-erb Aalpha gene simultaneously encodes a nuclear and a
mitochondrial T3 receptor (p43), thus ensuring coordination of the
expression of the mitochondrial genome and of nuclear genes
encoding mitochondrial proteins. Recent studies concerning the
physiological importance of the direct mitochondrial T3 pathway
involving p43 led to the conclusion that it is not only involved in
the regulation of fuel metabolism, but also in the regulation of
cell differentiation. As the processes leading to or resulting from
differentiation are energy-consuming, p43 coordination of
metabolism and differentiation could be of significant importance
in the regulation of development.
Regulation of mitochondrial biogenesis by thyroid hormone.
Authors
Weitzel JM, Iwen KA, Seitz HJ
Source
Experimental physiology 88:1 2003 Jan pg 121-8
Abstract
Thyroid hormone (T3) has a profound effect on mitochondrial
biogenesis. T3-regulated gene expression is mediated by thyroid
hormone receptor (TR) binding to thyroid hormone response elements
(TREs). In concert with the action of various coactivators and
corepressors this interaction leads to a modulation of the
chromatin structure and subsequently to a modulation of gene
expression of adjacent target genes.
http://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Mol%20Endocrinolhttp://www.unboundmedicine.com/medline/?st=M&author=Weitzel%20JMhttp://www.unboundmedicine.com/medline/?st=M&author=Iwen%20KAhttp://www.unboundmedicine.com/medline/?st=M&author=Seitz%20HJhttp://www.unboundmedicine.com/medline/?st=M&journal=Exp%20Physiol
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References 4 website: JMR, http://fluoroquinolonethyroid.com
However, as numerous genes are endogenously regulated by T3, and
a TRE appears to be absent in their regulatory elements, a
TR-independent pathway of T3-mediated gene regulation is likely. In
this review, we discuss the direct mechanisms of TR-dependent
regulation of gene expression on the nuclear and mitochondrial
genome by T3. We also summarize recent observations on an indirect
mechanism of T3 action via intermediate factor(s). We discuss the
regulation of nuclear respiratory factor 1 (NRF-1) and peroxisome
proliferator-activated receptor gamma coactivator 1 alpha
(PGC-1alpha) by T3, suggesting NRF-1 and PGC-1alpha as attractive
candidates for an intermediate factor of T3 action in vivo.
Triiodothyronine mitochondrial receptors: import and molecular
mechanisms.
Authors
Wrutniak-Cabello C, Carazo A, Casas F, Cabello G
Source
Journal de la Société de biologie 202:2 2008 pg 83-92
Abstract
Thyroid hormone exerts a diversity of physiological influences
over developmental and metabolic processes. Searching for receptors
able to mediate this extended regulation led to the identification
of triiodothyronine (T3) nuclear receptors encoded by two different
genes, c-erbA alpha (TR alpha) and c-erbA beta (TR beta). More
recently, two N-terminally truncated forms of the triiodothyronine
nuclear receptor TR alpha 1, with molecular weights of 43 and 28
kDa, have been discovered in mitochondria. Synthesized through the
use of internal initiation sites of translation occurring in the TR
alpha 1 transcript, they are addressed into mitochondria according
to an atypical process. Two mitochondrial import sequences have
been characterized in the C-terminal part of these proteins; in
addition, their N-terminal part, devoid of negative charges, plays
a permissive role in this import. Whereas the function of p28
remains unknown, p43 is a T3-dependent transcription factor of the
mitochondrial genome, acting through dimeric complexes involving at
least two other truncated forms of nuclear receptors, mtRXR and
mtPPAR. P43 activation by T3 stimulates mitochondrial protein
synthesis, respiratory chain activity and mitochondriogenesis.
Through the mitochondrial/nuclear crosstalk, this direct T3
mitochondrial pathway influences the expression of nuclear genes
involved in the regulation of cell proliferation and
differentiation. In particular, in myoblasts, p43 overexpression
stimulates terminal differentiation and induces a preferential
expression of slow myosin, by down-regulating c-Myc expression and
up-regulating calcineurin and myogenin expression. Comparison of
the respective influences of the nuclear and mitochondrial T3
pathways demonstrates either both additivity (myoblast
differentiation), complementarity (mitochondriogenesis, myoblast
differentiation) or opposite influences (myosin expression), thus
indicating that these two pathways introduce a fine-tuning of the
hormone influence.
Mitochondrial T3 receptor p43 regulates insulin secretion and
glucose homeostasis.
Authors
Blanchet E, Bertrand C, Annicotte JS, Schlernitzauer A,
Pessemesse L, Levin J, Fouret G, Feillet-Coudray C, Bonafos B,
Fajas L, Cabello G, Wrutniak-Cabello C, Casas F
Source
FASEB journal : official publication of the Federation of
American Societies for Experimental Biology 26:1 2012 Jan pg
40-50
http://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Carazo%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Soc%20Biolhttp://www.unboundmedicine.com/medline/?st=M&author=Blanchet%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Bertrand%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Annicotte%20JShttp://www.unboundmedicine.com/medline/?st=M&author=Schlernitzauer%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Levin%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Fouret%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Feillet-Coudray%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Feillet-Coudray%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Bonafos%20Bhttp://www.unboundmedicine.com/medline/?st=M&author=Fajas%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20J
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Abstract
Thyroid hormone is a major determinant of energy expenditure and
a key regulator of mitochondrial activity. We have previously
identified a mitochondrial triiodothyronine receptor (p43) that
acts as a mitochondrial transcription factor of the organelle
genome, which leads, in vitro and in vivo, to a stimulation of
mitochondrial biogenesis. Here we generated mice specifically
lacking p43 to address its physiological influence. We found that
p43 is required for normal glucose homeostasis. The p43(-/-) mice
had a major defect in insulin secretion both in vivo and in
isolated pancreatic islets and a loss of glucose-stimulated insulin
secretion. Moreover, a high-fat/high-sucrose diet elicited more
severe glucose intolerance than that recorded in normal animals. In
addition, we observed in p43(-/-) mice both a decrease in
pancreatic islet density and in the activity of complexes of the
respiratory chain in isolated pancreatic islets. These dysfunctions
were associated with a down-regulation of the expression of the
glucose transporter Glut2 and of Kir6.2, a key component of the
K(ATP) channel. Our findings establish that p43 is an important
regulator of glucose homeostasis and pancreatic β-cell function and
provide evidence for the first time of a physiological role for a
mitochondrial endocrine receptor.
Mice lacking the p43 mitochondrial T3 receptor become glucose
intolerant and insulin resistant during aging.
Authors
Bertrand C, Blanchet E, Pessemesse L, Annicotte JS,
Feillet-Coudray C, Chabi B, Levin J, Fajas L, Cabello G,
Wrutniak-Cabello C, Casas F
Source
PloS one 8:9 2013 pg e75111
Abstract
Thyroid hormones (TH) play an important regulatory role in
energy expenditure regulation and are key regulators of
mitochondrial activity. We have previously identified a
mitochondrial triiodothyronine (T3) receptor (p43) which acts as a
mitochondrial transcription factor of the organelle genome, which
leads in vitro and in vivo, to a stimulation of mitochondrial
biogenesis. Recently, we generated mice carrying a specific p43
invalidation. At 2 months of age, we reported that p43 depletion in
mice induced a major defect in insulin secretion both in vivo and
in isolated pancreatic islets, and a loss of glucose-stimulated
insulin secretion. The present study was designed to determine
whether p43 invalidation influences life expectancy and modulates
blood glucose and insulin levels as well as glucose tolerance or
insulin sensitivity during aging. We report that from 4 months old
onwards, mice lacking p43 are leaner than wild-type mice. p43-/-
mice also have a moderate reduction of life expectancy compared to
wild type. We found no difference in blood glucose levels, excepted
at 24 months old where p43-/- mice showed a strong hyperglycemia in
fasting conditions compared to controls animals. However, the loss
of glucose-stimulated insulin secretion was maintained whatever the
age of mice lacking p43. If up to 12 months old, glucose tolerance
remained unchanged, beyond this age p43-/- mice became increasingly
glucose intolerant. In addition, if up to 12 months old p43
deficient animals were more sensitive to insulin, after this age we
observed a loss of this capacity, culminating in 24 months old mice
with a decreased sensitivity to the hormone. In conclusion, we
demonstrated that during aging the depletion of the mitochondrial
T3 receptor p43 in mice progressively induced an increased glycemia
in the fasted state, glucose intolerance and an insulin-resistance
several features of type-2 diabetes.
http://www.unboundmedicine.com/medline/?st=M&author=Bertrand%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Blanchet%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Annicotte%20JShttp://www.unboundmedicine.com/medline/?st=M&author=Feillet-Coudray%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Chabi%20Bhttp://www.unboundmedicine.com/medline/?st=M&author=Levin%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Fajas%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&journal=PLoS%20One
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA
expression in human skeletal muscle without coordinated induction
of mitochondrial respiratory chain genes.
Authors
Barbe P, Larrouy D, Boulanger C, Chevillotte E, Viguerie N,
Thalamas C, Oliva Trastoy M, Roques M, Vidal H, Langin D
Source
FASEB journal : official publication of the Federation of
American Societies for Experimental Biology 15:1 2001 Jan pg
13-15
Abstract
Triiodothyronine (T3) increases mitochondrial respiration and
promotes the uncoupling between oxygen consumption and ATP
synthesis. T3 effect is mediated partly through transcriptional
control of genes encoding mitochondrial proteins. We determined the
effect of T3 on mRNA levels of uncoupling proteins (UCP) and
proteins involved in the biogenesis of the respiratory chain in
human skeletal muscle and on UCP2 mRNA expression in adipose
tissue. Ten young, healthy males received 75 to 100 5g of T3 per
day for 14 days. The increase in plasma-free T3 levels was
associated with an increase of resting metabolic rate and a
decrease of respiratory quotient. In skeletal muscle, treatment
with T3 induced a twofold increase of both UCP2 and UCP3 mRNA
levels (p c oxidase subunits 2 and 4, nuclear respiratory factor 1,
mitochondrial transcription factor A, and the co-activator PGC1 did
not change during the treatment. In adipose tissue, UCP2 mRNA
levels increased threefold. The direct effect of T3 on skeletal
muscle an d adipose tissue UCP2 and UCP3 mRNA expression was
demonstrated in vitro in human primary cultures. Our data show that
T3 induces UCP2 and UCP3 mRNA expression in humans. In skeletal
muscle, UCP regulation by T3 is not associated with the
transcriptional regulation of respiratory chain proteins.
Overexpression of the mitochondrial T3 receptor p43 induces a
shift in skeletal muscle fiber types.
Authors
Casas F, Pessemesse L, Grandemange S, Seyer P, Gueguen N, Baris
O, Lepourry L, Cabello G, Wrutniak-Cabello C
Source
PloS one 3:6 2008 pg e2501
Abstract
In previous studies, we have characterized a new hormonal
pathway involving a mitochondrial T3 receptor (p43) acting as a
mitochondrial transcription factor and consequently stimulating
mitochondrial activity and mitochondrial biogenesis. We have
established the involvement of this T3 pathway in the regulation of
in vitro myoblast differentiation. We have generated mice
overexpressing p43 under control of the human alpha-skeletal actin
promoter. In agreement with the previous characterization of this
promoter, northern-blot and western-blot experiments confirmed that
after birth p43 was specifically overexpressed in skeletal muscle.
As expected from in vitro studies, in 2-month old mice, p43
overexpression increased mitochondrial genes expression and
mitochondrial biogenesis as attested by the increase of
mitochondrial mass and mt-DNA copy number. In addition, transgenic
mice had a body
http://www.unboundmedicine.com/medline/?st=M&author=Barbe%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Larrouy%20Dhttp://www.unboundmedicine.com/medline/?st=M&author=Boulanger%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Chevillotte%20Ehttp://www.unboundmedicine.com/medline/?st=M&author=Viguerie%20Nhttp://www.unboundmedicine.com/medline/?st=M&author=Thalamas%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Oliva%20Trastoy%20Mhttp://www.unboundmedicine.com/medline/?st=M&author=Roques%20Mhttp://www.unboundmedicine.com/medline/?st=M&author=Vidal%20Hhttp://www.unboundmedicine.com/medline/?st=M&author=Langin%20Dhttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Grandemange%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Seyer%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Gueguen%20Nhttp://www.unboundmedicine.com/medline/?st=M&author=Baris%20Ohttp://www.unboundmedicine.com/medline/?st=M&author=Lepourry%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&journal=PLoS%20One
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References 4 website: JMR, http://fluoroquinolonethyroid.com
temperature 0.8 degrees C higher than control ones and displayed
lower plasma triiodothyronine levels. Skeletal muscles of
transgenic mice were redder than wild-type animals suggesting an
increased oxidative metabolism. In line with this observation, in
gastrocnemius, we recorded a strong increase in cytochrome oxidase
activity and in mitochondrial respiration. Moreover, we observed
that p43 drives the formation of oxidative fibers: in soleus
muscle, where MyHC IIa fibers were partly replaced by type I
fibers; in gastrocnemius muscle, we found an increase in MyHC IIa
and IIx expression associated with a reduction in the number of
glycolytic fibers type IIb. In addition, we found that PGC-1alpha
and PPARdelta, two major regulators of muscle phenotype were up
regulated in p43 transgenic mice suggesting that these proteins
could be downstream targets of mitochondrial activity. These data
indicate that the direct mitochondrial T3 pathway is deeply
involved in the acquisition of contractile and metabolic features
of muscle fibers in particular by regulating PGC-1alpha and
PPARdelta.
Depletion of the p43 mitochondrial T3 receptor in mice affects
skeletal muscle development and activity.
Authors
Pessemesse L, Schlernitzauer A, Sar C, Levin J, Grandemange S,
Seyer P, Favier FB, Kaminski S, Cabello G, Wrutniak-Cabello C,
Casas F
Source
FASEB journal : official publication of the Federation of
American Societies for Experimental Biology 26:2 2012 Feb pg
748-56
Abstract
In vertebrates, skeletal muscle myofibers display different
contractile and metabolic properties associated with different
mitochondrial content and activity. We have previously identified a
mitochondrial triiodothyronine receptor (p43) regulating
mitochondrial transcription and mitochondrial biogenesis. When
overexpressed in skeletal muscle, it increases mitochondrial DNA
content, stimulates mitochondrial respiration, and induces a shift
in the metabolic and contractile features of muscle fibers toward a
slower and more oxidative phenotype. Here we show that a p43
depletion in mice decreases mitochondrial DNA replication and
respiratory chain activity in skeletal muscle in association with
the induction of a more glycolytic muscle phenotype and a decrease
of capillary density. In addition, p43(-/-) mice displayed a
significant increase in muscle mass relative to control animals and
had an improved ability to use lipids. Our findings establish that
the p43 mitochondrial receptor strongly affects muscle mass and the
metabolic and contractile features of myofibers and provides
evidence that this receptor mediates, in part, the influence of
thyroid hormone in skeletal muscle.
Differential effects of thyroid hormones on energy metabolism of
rat slow- and fast-twitch muscles.
Authors
Bahi L, Garnier A, Fortin D, Serrurier B, Veksler V, Bigard AX,
Ventura-Clapier R
Source
Journal of cellular physiology 203:3 2005 Jun pg 589-98
Abstract
http://www.unboundmedicine.com/medline/?st=M&author=Pessemesse%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Schlernitzauer%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Sar%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Levin%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Grandemange%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Seyer%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Favier%20FBhttp://www.unboundmedicine.com/medline/?st=M&author=Kaminski%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Bahi%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Garnier%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Fortin%20Dhttp://www.unboundmedicine.com/medline/?st=M&author=Serrurier%20Bhttp://www.unboundmedicine.com/medline/?st=M&author=Veksler%20Vhttp://www.unboundmedicine.com/medline/?st=M&author=Bigard%20AXhttp://www.unboundmedicine.com/medline/?st=M&author=Ventura-Clapier%20Rhttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Cell%20Physiol
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Thyroid hormone (TH) is an important regulator of mitochondrial
content and activity. As mitochondrial content and properties
differ depending on muscle-type, we compared mitochondrial
regulation and biogenesis by T3 in slow-twitch oxidative (soleus)
and fast-twitch mixed muscle (plantaris). Male Wistar rats were
treated for 21 to 27 days with T3 (200 microg/kg/day). Oxidative
capacity, regulation of mitochondrial respiration by substrates and
phosphate acceptors, and transcription factors were studied. In
soleus, T3 treatment increased maximal oxygen consumption (Vmax)
and the activities of citrate synthase (CS) and cytochrome oxidase
(COX) by 100%, 45%, and 71%, respectively (P < 0.001), whereas
in plantaris only Vmax increased, by 39% (P < 0.01).
ADP-independent respiration rate was increased in soleus muscle by
216% suggesting mitochondrial uncoupling. Mitochondrial substrate
utilization in soleus was also influenced by T3, as were
mitochondrial enzymes. Lactate dehydrogenase (LDH) activity was
elevated in soleus and plantaris by 63% and 11%, respectively (P
< 0.01), and soleus creatine kinase was increased by 48% (P <
0.001). T3 increased the mRNA content of the transcriptional
co-activator of mitochondrial genes, PGC-1alpha, and the I and IV
COX subunits in soleus. The muscle specific response to thyroid
hormones could be explained by a lower content of TH receptors in
plantaris than soleus. Moreover, TRalpha mRNA level decreased
further after T3 treatment. These results demonstrate that TH has a
major effect on mitochondrial content, regulation and coupling in
slow oxidative muscle, but to a lesser extent in fast muscle, due
to the high expression of TH receptors and PGC-1alpha transcription
factor.
Regulation of fibronectin by thyroid hormone receptors.
Lin KH, Chen CY, Chen SL, Yen CC, Huang YH, Shih CH, Shen JJ,
Yang RC, Wang CS
Source
Journal of molecular endocrinology 33:2 2004 Oct pg 445-58
(My note from Wiki: insoluble cellular fibronectin is a major
component of the extracellular matrix. It is secreted by various
cells, primarily fibroblasts, as a soluble protein dimer and is
then assembled into an insoluble matrix in a complex cell-mediated
process. Fibronectin is a high-molecular weight (~440kDa)
glycoprotein of the extracellular matrix that binds to
membrane-spanning receptor proteins called integrins. Similar to
integrins, fibronectin binds extracellular matrix components such
as collagen.)
Abstract
Thyroid hormones regulate growth, development, differentiation,
and metabolic processes by interacting with and activating thyroid
hormone receptors and associated pathways. We investigated the
triiodothyronine (T3) modulation of gene expression, in human
hepatocellular carcinoma cell lines, via a PCR-based cDNA
subtraction method. Here we present further data on one of the
T3-upregulated genes, fibronectin (FN). We demonstrate that the
induction of FN protein expression by T3 in TRalpha1 and TRbeta1
over-expressing cells was time and dose-dependent at the mRNA and
protein levels. Blockade of protein synthesis by cycloheximide
almost completely inhibited the concomitant induction of FN mRNA by
T3, indicating that T3 indirectly regulates FN. Furthermore,
nuclear-run on and FN promoter assay clearly can specifically
increase the number of FN transcriptional demonstrated that the
presence of T3 initiations. In addition, we further confirmed that
the up-regulation of FN by T3 was mediated, at least in part, by
transforming growth factor-beta (TGF-beta), because the induction
of FN was blocked in a dose-dependent manner by the addition of
TGF-beta neutralizing antibody. In an effort to elucidate the we
demonstrated the involvement of the signaling pathways involved in
the activation of FN by T3, mitogen activated protein kinase/c-Jun
N-terminal kinase/p38 MAPK (MAPK/JNK/p38) pathway. Although T3
induces the expression of TGF-beta, neither wild-type nor
dominant-negative Smad3 or Smad4 over-expression affected the
activation of FN by T3. Thus, we demonstrate that T3 regulates FN
gene expression indirectly at the transcriptional level, with the
participation of the MAPK/JNK/p38 pathway and the TGF-beta
signaling pathway but independent of Smad3/4.
http://www.unboundmedicine.com/medline/?st=M&author=Lin%20KHhttp://www.unboundmedicine.com/medline/?st=M&author=Chen%20CYhttp://www.unboundmedicine.com/medline/?st=M&author=Chen%20SLhttp://www.unboundmedicine.com/medline/?st=M&author=Yen%20CChttp://www.unboundmedicine.com/medline/?st=M&author=Huang%20YHhttp://www.unboundmedicine.com/medline/?st=M&author=Shih%20CHhttp://www.unboundmedicine.com/medline/?st=M&author=Shen%20JJhttp://www.unboundmedicine.com/medline/?st=M&author=Yang%20RChttp://www.unboundmedicine.com/medline/?st=M&author=Wang%20CShttp://www.unboundmedicine.com/medline/?st=M&journal=J%20Mol%20Endocrinol
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Thyroid hormones and mitochondria.
Authors
Goglia F, Silvestri E, Lanni A
Abstract
Because of their central role in the regulation of
energy-transduction, mitochondria, the major site of
oxidative processes within the cell, are considered a likely
subcellular target for the action that thyroid
hormones exert on energy metabolism. However, the mechanism
underlying the regulation of basal
metabolic rate (BMR) by thyroid hormones still remains unclear.
It has been suggested that these
hormones might uncouple substrate oxidation from ATP synthesis,
but there are no clear-cut data to
support this idea. Two iodothyronines have been identified as
effectors of the actions of thyroid
hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3)
and 3,5-diiodo-L-thyronine (T2). Both
have significant effects on BMR, but their mechanisms of action
are not identical. T3 acts on the nucleus
to influence the expression of genes involved in the regulation
of cellular metabolism and mitochondria
function; 3,5-T2, on the other hand, acts by directly
influencing the mitochondrial energy-transduction
apparatus. A molecular determinant of the effects of T3 could be
uncoupling protein-3 (UCP-3), while
the cytochrome-c oxidase complex is a possible target for
3,5-T2. In conclusion, it is likely that
iodothyronines regulate energy metabolism by both short-term and
long-term mechanisms, and that
they act in more than one way in affecting mitochondrial
functions.
The Triiodothyronine Mitochondrial Pathway
C. Wrutniak, P. Rochard, F. Casas, G. Cabello
Abstract
Numerous data show that mitochondrial activity is hormonally
regulated. Besides the influence
of α-agonists, glucagon and vasopressin, several studies show
that glucocorticoid, thyroid
hormone, vitamin D3 and peroxisome proliferators stimulate the
activity of this organelle.
Interestingly, thyroid hormone, glucocorticoid, peroxisome
proliferators and vitamin D3
receptors all belong to a common nuclear receptor superfamily.
These data suggest that such
receptors could have a particular importance in the regulation
of mitochondrial activity.
However, the mechanisms involved in this endocrine influence
remain poorly understood. The
action of thyroid hormone, especially triiodothyronine (T3),
upon the organelle has been studied,
leading to the proposition of a direct T3 mitochondrial pathway.
In this paper, we present
numerous data in agreement with this hypothesis, with special
reference to recent work from our
laboratory identifying a T3 binding protein in the mitochondrial
matrix.
http://link.springer.com/search?facet-author=%22C.+Wrutniak%22http://link.springer.com/search?facet-author=%22P.+Rochard%22http://link.springer.com/search?facet-author=%22F.+Casas%22http://link.springer.com/search?facet-author=%22G.+Cabello%22
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Modification of nucleic acid levels per mitochondrion induced by
thyroidectomy or
triiodothyronine administration
T. De Leo, S. Di Meo, A. Barletta, G. Martino, F. Goglia
Summary
The authors have determined the liver mitochondrial population
(number of
mitochondria/nucleus) in young rats, which has been
thyroidectomized ( T¯ ) or thyroidectomized and subsequently
treated with triiodothyronine (T3). They have observed that
thyroidectomy decreased such a population to 72.3% with respect
to the normal one, while the T3
administration (at the dose of 10 μg/100 g body weight every
second day, from day 50 to day 60
of age) restored the mitochondria number to 81.8% of normal
ones.
The average levels of proteins per mitochondrion were
8.90×10−13
g in the liver of normal 60-
day-old rats. This content was doubled in T¯ rats of the same
age while the levels of nucleic acids or the nucleic acid
polymerase activities per mitochondrion were enhanced,
notwithstanding that the specific values (referred to mg
mitochondrial protein) decreased. The T3
administration severely lowered the content of protein per
mitochondrion, and this may indicate
that thyroid hormones control the normal assemblage of
mitochondrial protein.
Thyroid control over biomembranes. VII. Heart muscle
mitochondria from -
triiodothyronine-injected rats
Hoch, Frederic L.
1982-02
Citation: Hoch, Frederic L. (1982/02)."Thyroid control over
biomembranes. VII. Heart muscle
mitochondria from -triiodothyronine-injected rats." Journal of
Molecular and Cellular Cardiology 14(2):
81-90.
Abstract: Mitochondria prepared from the myocardia of rats
injected with -triiodothyronine, 1 [mu]g/g
body weight daily for 3 days, were compared with those from
euthyroid or hypothyroid animals. The
heart weights of the hormonetreated animals increased 37%,
whereas mitochondrial yield remained
unchanged. Oxidative phosphorylation measured at 25[deg]C
featured a decreased rate of
phosphorylating (State 3) respiration with normal
phosphorylative efficiency (ADP: O ratio). The
http://link.springer.com/search?facet-author=%22T.+De+Leo%22http://link.springer.com/search?facet-author=%22S.+Di+Meo%22http://link.springer.com/search?facet-author=%22A.+Barletta%22http://link.springer.com/search?facet-author=%22G.+Martino%22http://link.springer.com/search?facet-author=%22F.+Goglia%22
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References 4 website: JMR, http://fluoroquinolonethyroid.com
respiratory deficit was connected with a progressive loss as the
mitochondria stood in iced suspensions;
control mitochondrial respiration decreased 0.26-times as fast.
The lipid composition of the heart
mitochondria of the thyrotoxic group was abnormal in that the
excess of neutral lipids (probably
triglycerides) had a high content of oleoyl residues. Their
phospholipid group compositions and the fatty
acyl contents of each of the phospholipid classes were similar
to control compositions, in contrast to the
excess linoleoyl and decreased arachidonoyl contents of the
phosphatidylcholines in the hypothyroid
group. Thus the abnormalities of heart mitochondrial function
are connected with different patterns of
lipid changes in hyperthyroidism and hypothyroidism. Evidence
for a relationship of organelle lipids to
the reported abnormal myocardial contractile performance in
these thyroid states is discussed. [less]
DOIs: http://dx.doi.org/10.1016/0022-2828(82)90196-1
Effects of triiodothyronine on oxidative phosphorylation in
immature rat brain mitochondria
1. DAVID HOLTZMAN, Ph.D., M. D. and 2. CYRIL L. MOORE, Ph.D.
Abstract
Article abstract Oxidative phosphorylation was measured
polarographically in brain mitochondria
isolated from 1 to 3-week-old normal and
triiodothyronine-treated rat pups. Adenosine diphosphate
(ADP)/oxygen ratios with nicotinamide-adenine dinucleotide
(NAD)-linked substrates, but not with
succinate, were increased in brain mitochondria from
experimental animals at each age. Control ratios
and respiratory rates were not affected. Thus, the normal
maturational increase in ADP/oxygen ratios
with NAD-linked substrates is accelerated in brain mitochondria
from rats treated with triiodothyronine
from birth. This effect on efficiency of oxidative
phosphorylation is similar to that of thyroid hormones
on other properties of the maturing brain.
© 1977 by the American Academy of Neurology
Triiodothyronine Prevents Cardiac Ischemia/Reperfusion
Mitochondrial Impairment and Cell Loss by Regulating miR30a/p53
Axis
Francesca Forini, Claudia Kusmic, Giuseppina Nicolini, Laura
Mariani, Riccardo Zucchi, Marco Matteucci, Giorgio Iervasi, and
Letizia Pitto
DOI: http://dx.doi.org/10.1210/en.2014-1106
Received: February 05, 2014
Accepted: July 24, 2014
Published Online: August 19, 2014
http://dx.doi.org/http:/dx.doi.org/10.1016/0022-2828(82)90196-1http://press.endocrine.org/action/doSearch?text1=Forini%2C+F&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Kusmic%2C+C&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Nicolini%2C+G&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Mariani%2C+L&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Zucchi%2C+R&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Matteucci%2C+M&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Iervasi%2C+G&field1=Contribhttp://press.endocrine.org/action/doSearch?text1=Pitto%2C+L&field1=Contribhttp://dx.doi.org/10.1210/en.2014-1106
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References 4 website: JMR, http://fluoroquinolonethyroid.com
Abstract
Mitochondrial dysfunctions critically affect cardiomyocyte
survival during ischemia/reperfusion (I/R)
injury. In this scenario p53 activates multiple signaling
pathways that impair cardiac mitochondria and
promote cell death. p53 is a validated target of miR-30 whose
levels fall under ischemic conditions.
Although triiodothyronine (T3) rescues post-ischemic
mitochondrial activity and cell viability, no data
are available on its role in the modulation of p53 signaling in
I/R. Here we test the hypothesis that early
T3 supplementation in rats inhibits the post I/R activation of
p53 pro-death cascade through the
maintenance of miRNA 30a expression.
In our model, T3 infusion improves the recovery of post-ischemic
cardiac performance. At the molecular
level, the beneficial effect of T3 is associated with restored
levels of miR-30a expression in the area at
risk (AAR) that correspond to p53 mRNA downregulation. The
concomitant decrease in p53 protein
content reduces Bax expression and limits mitochondrial membrane
depolarization resulting in
preserved mitochondrial function and decreased apoptosis and
necrosis extent in the AAR. Also in
primary cardiomyocyte culture of neonatal rats, T3 prevents both
miR-30a downregulation and p53
raise induced by hypoxia. The regulatory effect of T3 is greatly
suppressed by miR-30a knockdown.
Overall these data suggest a new mechanism of T3-mediated
cardioprotection that is targeted to
mitochondria and acts, at least in part, through the regulation
of miR-30a/p53 axis.
Affiliations
Consiglio Nazionale delle Ricerche (CNR) Institute of Clinical
Physiology (F.F., C.K., G.N., L.M., G.I., L.P),
Via G. Moruzzi 1, Pisa, Italy; Department of Pathology (R.Z.,
G.I.), University of Pisa, 56127 Pisa, Italy;
Scuola Superiore Sant'Anna (M.M., G.I.), Piazza Martiri della
Libertà 33, 56127 Pisa, Italy; and
CNR/Tuscany Region G Monasterio Foundation (G.I.), Via G.
Moruzzi 1, 56124 Pisa, Italy
A Variant Form of the Nuclear Triiodothyronine Receptor
c-ErbAα1
Plays a Direct Role in Regulation of Mitochondrial RNA
Synthesis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC84876/
1. François Casas1,
2. Pierrick Rochard1,
3. Anne Rodier1,
4. Isabelle Cassar-Malek1,
5. Sophie Marchal-Victorion1,
6. Rudolf J. Wiesner2,
7. Gérard Cabello1,*, and
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC84876/http://mcb.asm.org/search?author1=Fran%C3%A7ois+Casas&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Fran%C3%A7ois+Casas&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Pierrick+Rochard&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Pierrick+Rochard&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Anne+Rodier&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Anne+Rodier&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Isabelle+Cassar-Malek&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Isabelle+Cassar-Malek&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Sophie+Marchal-Victorion&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Sophie+Marchal-Victorion&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Rudolf+J.+Wiesner&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Rudolf+J.+Wiesner&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=G%C3%A9rard+Cabello&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=G%C3%A9rard+Cabello&sortspec=date&submit=Submithttp://mcb.asm.org/content/19/12/7913.full#fn-1
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References 4 website: JMR, http://fluoroquinolonethyroid.com
8. Chantal Wrutniak1
+ Author Affiliations
1. Institut National de la Recherche Agronomique, Unité
d’Endocrinologie Cellulaire, Laboratoire
de Différenciation Cellulaire et Croissance, 34060 Montpellier
Cedex 1, France,1 and
2. Physiologisches Institut, Universität Heidelberg, D-69120
Heidelberg, Germany2
Next Section
ABSTRACT
In earlier research, we identified a 43-kDa c-ErbAα1 protein
(p43) in the mitochondrial matrix of rat
liver. In the present work, binding experiments indicate that
p43 displays an affinity for
triiodothyronine (T3) similar to that of the T3 nuclear
receptor. Using in organello import
experiments, we found that p43 is targeted to the organelle by
an unusual process similar to that
previously reported for MTF1, a yeast mitochondrial
transcription factor. DNA-binding experiments
demonstrated that p43 specifically binds to four mitochondrial
DNA sequences with a high similarity
to nuclear T3 response elements (mt-T3REs). Using in organello
transcription experiments, we
observed that p43 increases the levels of both precursor and
mature mitochondrial transcripts and
the ratio of mRNA to rRNA in a T3-dependent manner. These events
lead to stimulation of
mitochondrial protein synthesis. In transient-transfection
assays with reporter genes driven by the
mitochondrial D loop or two mt-T3REs located in the D loop, p43
stimulated reporter gene activity
only in the presence of T3. All these effects were abolished by
deletion of the DNA-binding domain
of p43. Finally, p43 overexpression in QM7 cells increased the
levels of mitochondrial mRNAs, thus
indicating that the in organello influence of p43 was
physiologically relevant. These data reveal a
novel hormonal pathway functioning within the mitochondrion,
involving a truncated form of a
nuclear receptor acting as a potent mitochondrial T3-dependent
transcription factor.
The regulation of mitochondrial activity by thyroid hormone is
well documented. Triiodothyronine
(T3) increases the number of mitochondria (20, 24-25) and
mitochondrial protein synthesis (33).
This hormone is thus considered to be a major regulator of
mammalian mitochondrial biogenesis
(33). T3 also stimulates mitochondrial metabolism (46) and, in
particular, oxidative phosphorylation
(48,50).
Triiodothyronine modulates the expression of aquaporin-8 in rat
liver mitochondria
1. Giuseppe Calamita,
2. Maria Moreno1,
3. Domenico Ferri2,
4. Elena Silvestri1,
http://mcb.asm.org/search?author1=Chantal+Wrutniak&sortspec=date&submit=Submithttp://mcb.asm.org/search?author1=Chantal+Wrutniak&sortspec=date&submit=Submithttp://mcb.asm.org/content/19/12/7913.fullhttp://mcb.asm.org/content/19/12/7913.full#sec-1http://mcb.asm.org/content/19/12/7913.full#ref-20http://mcb.asm.org/content/19/12/7913.full#ref-24http://mcb.asm.org/content/19/12/7913.full#ref-33http://mcb.asm.org/content/19/12/7913.full#ref-33http://mcb.asm.org/content/19/12/7913.full#ref-46http://mcb.asm.org/content/19/12/7913.full#ref-48http://mcb.asm.org/content/19/12/7913.full#ref-50http://joe.endocrinology-journals.org/search?author1=Giuseppe+Calamita&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Maria+Moreno&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Maria+Moreno&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Domenico+Ferri&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Domenico+Ferri&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Elena+Silvestri&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Elena+Silvestri&sortspec=date&submit=Submit
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References 4 website: JMR, http://fluoroquinolonethyroid.com
5. Patrizia Roberti,
6. Luigi Schiavo1,
7. Patrizia Gena,
8. Maria Svelto and
9. Fernando Goglia1
+ Author Affiliations
1. Department of General and Environmental Physiology,
Università degli Studi di Bari,
Via Amendola 165/A, 70126 Bari, Italy
2. 1Department of Biological and Environmental Sciences,
University of Sannio, Via
Port’Arsa 11, 82100 Benevento, Italy
3. 2Department of Zoology, University of Bari, Bari, Italy
1. (Requests for offprints should be addressed to G Calamita;
Email: [email protected])
Next Section
Abstract
The recent identification of aquaporin-8 (AQP8), an aquaporin
(AQP) channel permeable to water and
ammonia, in the inner membrane (IMM) of rat liver mitochondria
suggested a role for such AQP in
the hydration state and the metabolic function of mitochondria.
Since thyroid hormone
triiodothyronine (T3) is known to modulate both the shape and
the metabolic activities of liver
mitochondria, it was interesting to investigate the expression
and distribution of AQP8 as well as the
osmotic water permeability of the IMM in liver mitochondria from
rats in different thyroid states. By
semi-quantitative reverse transcriptase (RT)-PCR, when compared
with the euthyroid counterpart,
the levels of hepatic AQP8 mRNA significantly increased in the
hypothyroid state, whereas they were
strongly decreased after administration of T3. A similar pattern
was seen at the protein level by
immunoblotting mitochondrial membranes. The upregulation of
mitochondrial AQP8 in the
hypothyroid liver was confirmed by immunogold electron
microscopy. Stopped-flow light scattering
with IMM vesicles showed no significant differences in terms of
osmotic water permeability among
the IMMs in the various thyroid states. Overall, our data
indicate that the T3 modulation of the AQP8
gene is a rapid downregulation of transcription. Modulation of
hepatic AQP8 expression may be
relevant to the regulation of mitochondrial metabolism by
thyroid hormones.
Previous SectionNext Section
Introduction
Triiodothyronine (T3) exerts significant actions on energy
metabolism, with mitochondria being a
major target for its effects (Soboll 1993). Extensive changes
occur in the mitochondrial compartment
in response either to thyroid hormone administration or to
physiological states modulating thyroid
gland activity (e.g. cold exposure, aging, dietary changes;
Goglia et al. 1999). Indeed, alterations to
the thyroid state of animals have considerable effects on the
synthesis (Roodyn 1965, Goglia et al.
1988), the turnover (Gross 1971), and the functional capacity of
mitochondrial components. Liver
mitochondria from hypothyroid rats have a decreased activity of
membrane-associated electron
http://joe.endocrinology-journals.org/search?author1=Patrizia+Roberti&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Luigi+Schiavo&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Luigi+Schiavo&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Patrizia+Gena&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Maria+Svelto&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Fernando+Goglia&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/search?author1=Fernando+Goglia&sortspec=date&submit=Submithttp://joe.endocrinology-journals.org/content/192/1/111.fullmailto:[email protected]://joe.endocrinology-journals.org/content/192/1/111.full#sec-1http://joe.endocrinology-journals.org/content/192/1/111.full#abstract-1http://joe.endocrinology-journals.org/content/192/1/111.full#abstract-1http://joe.endocrinology-journals.org/content/192/1/111.full#ref-44http://joe.endocrinology-journals.org/content/192/1/111.full#ref-15http://joe.endocrinology-journals.org/content/192/1/111.full#ref-39http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-16
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References 4 website: JMR, http://fluoroquinolonethyroid.com
transport enzymes and anion carriers (Paradies et al. 1994), a
failure that has been ascribed to a
lower expression of their corresponding proteins as well as to
changes in the composition of the
inner membrane (Soboll et al. 1994, Schonfeld et al. 1997).
Thyroid hormones are also known to
modulate both shape and metabolic efficiency of mitochondria
(Jakovcic et al. 1978, Goglia et al.
1988). However, although marked differences in the shape and the
number of the cristae have been
reported in the liver mitochondria of rats in different thyroid
states (Jakovcic et al. 1978, Goglia et al.
1989), the molecular mechanisms underlying T3 modulation of
mitochondrial morphology remain
mostly elusive. A clue to understanding such mechanisms relates
to the fact that mitochondria are
well-behaved osmometers and that their shape is influenced by
the movement of water
accompanying the net transport of solutes into and out of their
matrix (Beavis et al. 1985).
Endocrine regulation of mitochondrial activity: involvement of
truncated RXRalpha and c-Erb Aalpha1 proteins.
Authors
Casas F, Daury L, Grandemange S, Busson M, Seyer P, Hatier R,
Carazo A, Cabello G, Wrutniak-Cabello C
Source
FASEB journal : official publication of the Federation of
American Societies for Experimental Biology 17:3 2003 Mar pg
426-36
Abstract
The importance of mitochondrial activity has recently been
extended to the regulation of developmental processes. Numerous
pathologies associated with organelle's dysfunctions emphasize
their physiological importance. However, regulation of
mitochondrial genome transcription, a key element for organelle's
function, remains poorly understood. After characterization in the
organelle of a truncated form of the triiodothyronine nuclear
receptor (p43), a T3-dependent transcription factor of the
mitochondrial genome, our purpose was to search for other
mitochondrial receptors involved in the regulation of organelle
transcription. We show that a 44 kDa protein related to RXRalpha
(mt-RXR), another nuclear receptor, is located in the mitochondrial
matrix. We found that mt-RXR is produced after cytosolic or
intramitochondrial enzymatic cleavage of the RXRalpha nuclear
receptor. After mitochondrial import and binding to specific
sequences of the organelle genome, mt-RXR induces a
ligand-dependent increase in mitochondrial RNA levels. mt-RXR
physically interacts with p43 and acts alone or through a
heterodimerical complex activated by 9-cis-retinoic acid and T3 to
increase RNA levels. These data indicate that hormonal regulation
of mitochondrial transcription occurs through pathways similar to
those that take place in the nucleus and open a new way to better
understand hormone and vitamin action at the cellular level.
Effect of thyroid hormone on the myosin heavy chain isoforms in
slow and fast muscles of the rat.
Authors
Jakubiec-Puka A, Ciechomska I, Mackiewicz U, Langford J,
Chomontowska H
Source
Acta biochimica Polonica 46:3 1999 pg 823-35
Abstract
http://joe.endocrinology-journals.org/content/192/1/111.full#ref-38http://joe.endocrinology-journals.org/content/192/1/111.full#ref-45http://joe.endocrinology-journals.org/content/192/1/111.full#ref-41http://joe.endocrinology-journals.org/content/192/1/111.full#ref-24http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-13http://joe.endocrinology-journals.org/content/192/1/111.full#ref-24http://joe.endocrinology-journals.org/content/192/1/111.full#ref-14http://joe.endocrinology-journals.org/content/192/1/111.full#ref-14http://joe.endocrinology-journals.org/content/192/1/111.full#ref-1http://www.unboundmedicine.com/medline/?st=M&author=Casas%20Fhttp://www.unboundmedicine.com/medline/?st=M&author=Daury%20Lhttp://www.unboundmedicine.com/medline/?st=M&author=Grandemange%20Shttp://www.unboundmedicine.com/medline/?st=M&author=Busson%20Mhttp://www.unboundmedicine.com/medline/?st=M&author=Seyer%20Phttp://www.unboundmedicine.com/medline/?st=M&author=Hatier%20Rhttp://www.unboundmedicine.com/medline/?st=M&author=Carazo%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Cabello%20Ghttp://www.unboundmedicine.com/medline/?st=M&author=Wrutniak-Cabello%20Chttp://www.unboundmedicine.com/medline/?st=M&journal=FASEB%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Jakubiec-Puka%20Ahttp://www.unboundmedicine.com/medline/?st=M&author=Ciechomska%20Ihttp://www.unboundmedicine.com/medline/?st=M&author=Mackiewicz%20Uhttp://www.unboundmedicine.com/medline/?st=M&author=Langford%20Jhttp://www.unboundmedicine.com/medline/?st=M&author=Chomontowska%20Hhttp://www.unboundmedicine.com/medline/?st=M&journal=Acta%20Biochim%20Pol
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References 4 website: JMR, http://fluoroquinolonethyroid.com
The myosin heavy chain (MHC) was studied by biochemical methods
in the slow-twitch (soleus) and two fast-twitch leg muscles of the
triiodothyronine treated (hyperthyroid), thyroidectomized
(hypothyroid) and euthyroid (control) rats. The changes in the
contents of individual MHC isoforms(MHC-1, MHC-2A, MHC-2B and
MHC-2X) were evaluated in relation to the muscle mass and the total
MHC content. The MHC-1 content decreased in hyperthyreosis, while
it increased in hypothyreosis in the soleus and in the fast
muscles. The MHC-2A content increased in hyperthyreosis and it
decreased in hypothyreosis in the soleus muscle. In the fast
muscles hyperthyreosis did not affect the MHC-2A content, whereas
hypothyreosis caused an increase in this MHC isoform content. The
MHC-2X, present only in traces or undetected in the control soleus
muscle, was synthesised in considerable amount in hyperthyreosis;
in hypothyreosis the MHC-2X was not detected in the soleus. In the
fast muscles the content of MHC-2X was not affected by any changes
in the thyroid hormone level. The MHC-2B seemed to be not
influenced by hyperthyreosis in the fast muscles, whereas the
hypothyreosis caused a decrease of its content. In the soleus
muscle the MHC-2B was not detected in any groups of rats. The
results suggest that the amount of each of the four MHC isoforms
expressed in the mature rat leg muscles is influenced by the
thyroid hormone in a different way. The MHC-2A and the MHC-2X are
differently regulated in the soleus and in the fast muscles;
thyroid hormone seems to be necessary for expression of those
isoforms in the soleus muscle.
Thyroid Hormone Binding by a Component of mitochondrial
membrane
Proceedings of the National Academy of Sciences of the United
States of America © 1975 National
Academy of Sciences
Abstract:
The thyroid hormone, triiodothyronine, has been shown to be
bound by the intranuclear
chromatin protein associated with active DNA, where it is
believed to stimulate transcription.
Evidence exists that the thyroid hormones have direct action not
only on nuclei, but also on
mitochondria. Therefore, specific proteins that bind thyroid
hormones in the mitochondria should
be demonstrable. Mitochondria were isolated from homogenized rat
livers by sedimentation
through 0.25 M sucrose solution, followed by washing four times
to free them of microsomes.
Strong binding of thyroid hormones was observed in mitochondrial
fractions prepared from both
the membranes and the matrix. After incubation in an ice bath
with increasing amounts of
triiodothyronine with added tracer [125I]triiodothyronine, the
matrix infrequently contained
specific saturable receptor sites, but usually exhibited strong
``nonspecific'' interaction. In
contrast, a protein fraction obtained from the mitochondrial
membranes revealed on Scatchard
plot an association constant approximating 4 × 109 liters/M,
significantly higher than that we
have obtained for isolated rat liver nuclei (about 5 × 108
liters/M). Partial purification of the
mitochondrial membrane protein resulted in pronounced diminution
of ``nonspecific binding''
and a higher apparent association constant (ka greater than 1011
liters/M). The demonstration of
a triiodothyronine binding protein in the mitochondrial membrane
is consistent with direct
hormone action upon mitochondria. The binding sites of nuclei
and mitochondria both exhibit
saturability, and are considered to have a role in hormone
action. The nuclear protein binding is
believed to influence growth, development, and functions
concerned with cell maintenance,
whereas mitochondrial protein binding is probably concerned with
reversible effects on energy
metabolism.
http://www.jstor.org/action/showPublisher?publisherCode=nashttp://www.jstor.org/action/showPublisher?publisherCode=nas
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References 4 website: JMR, http://fluoroquinolonethyroid.com
"Mild" Uncoupling of Mitochondria A. A. Starkov Received January
10, 1997 Recently, it was proposed that the thyroid
hormone-mediated uncoupling in mitochondria is involved
in the cellular defence system against free radicals (Skulachev
V.P. (1996) Quart. Rev. Biophys.
29:169-202). This phenomenon was named "mild" uncoupling. It was
postulated to be a protein mediated
process controlled by several factors. The data reported during
the past 40 years, pointing to
the protein-mediated uncoupling mechanism in mitochondria, are
reviewed in a context of
hypothetical properties of "mild" uncoupling. The mechanism of
"mild" uncoupling is suggested to be
the following: (a) mitochondria possess protein(s) that regulate
the proton permeability of inner
mitochondrial membrane; (b) these proteins are regulated by
binding of an unidentified low molecular- weight endogenous
compound with properties resembling those of the most active
artificial
uncouplers like FCCP and SF6847; (c) the interaction of this
compound with its target protein(s) is
modulated by a thyroid hormone in a positive (i.e. enhancing the
proton permeability) way and by sex
steroid hormones in a negative way; (e) endogenous fatty acids
can attenuate the influence of both
thyroid and steroid hormones.
KEY WORDS: Uncoupling; mitochondria; free radicals; thyroid
hormones; steroid hormones
Effect of Calcium Ion on Triiodothyronine Binding to Kidney
Outer Mitochondrial
Membrane in vitro
KIYOSHI HASHIZUME, KAZUO ICHIKAWA AND MUTSUHIRO KOBAYASHI
Department of Gerontology, Endocrinology and Metabolism,
Shinshu University School of Medicine, Matsumoto 390
Abstract
The effect of calcium ion on 3,5,3'-triiodothyronine (T3)
binding to rat kidney outer mitochondrial
membranes was examined in vitro. The outer mitochondrial
membranes were prepared by using a
discontinuous sucrose density gradient centrifugation. The
membrane fraction, which is enriched with
monoamine oxidase activity, contained specific binding sites for
T3. Scatchard analysis of T3 binding to
outer mitochondrial membranes gave an association constant (Ka)
of 0.53 •~ 1010M-1. The binding of
[125I]-T3 to the membranes was inhibited by the addition of
CaCl2(0.25 •~ 10-4-2.5 •~ 10-3M). 50%
inhibition was obtained by 0.75 x 10-4M CaC12 in the presence of
0.1 mM EGTA. When outer
mitochondrial membranes were solubilized with Triton X-100, four
main T3 binding activities were
isolated by a gel filtration study. On the other hand, the
binding of [125I]-T3 to the solubilized T3
receptors derived from outer mitochondrial membranes was not
strongly inhibited by calcium. When
outer mitochondrial membranes were preincubated in the presence
of 1 mM calcium, the number of T3
binding sites in the membranes was decreased, and this was
associated with an increase in the number
of T3 binding sites in the supernatants of the incubation
mixture. Scatchard analysis showed that the
number of T3 binding sites in the membranes is decreased by
calcium ion without any change in the
association constant. In studies with gel filtration of
receptors which are released by Ca2+ from outer
mitochondrial membranes, three main T3 binding activities were
isolated. Mg2+, Mn2+, Zn2+ and Cu2+
did not affect T3 binding to outer mitochondrial membranes. The
results indicate that calcium ion
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References 4 website: JMR, http://fluoroquinolonethyroid.com
regulates T3 binding to the outer mitochondrial membrane through
the release of T3 receptors from the
membranes.
Mol Cell Endocrinol. 2013 Oct 15;379(1-2):51-61. doi:
10.1016/j.mce.2013.06.006. Epub 2013 Jun 13.
Thyroid hormones and mitochondria: with a brief look at
derivatives and analogues.
Cioffi F1, Senese R, Lanni A, Goglia F.
Author information
1Dipartimento di Scienze e Tecnologie, Università degli Studi
del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy.
Abstract
Thyroid hormones (TH) have a multiplicity of effects. Early in
life, they mainly affect development and differentiation, while
later on they have particularly important influences over metabolic
processes in almost all tissues. It is now quite widely accepted
that thyroid hormones have two types of effects on mitochondria.
The first is a rapid stimulation of respiration, which is evident
within minutes/hours after hormone treatment, and it is probable
that extranuclear/non-genomic mechanisms underlie this effect. The
second response occurs one to several days after hormone treatment,
and leads to mitochondrial biogenesis and to a change in
mitochondrial mass. The hormone signal for the second response
involves both T3-responsive nuclear genes and a direct action of T3
at mitochondrial binding sites. T3, by binding to a specific
mitochondrial receptor and affecting the transcription apparatus,
may thus act in a coordinated manner with the T3 nuclear pathway to
regulate mitochondrial biogenesis and turnover. Transcription
factors, coactivators, corepressors, signaling pathways and,
perhaps, all play roles in these mechanisms. This review article
focuses chiefly on TH, but also looks briefly at some analogues and
derivatives (on which the data is still somewhat patchy). We
summarize data obtained recently and in the past to try to obtain
an updated picture of the current research position concerning the
metabolic effects of TH, with particular emphasis on those exerted
via mitochondria.
Mutat Res. 1989 Mar;211(1):171-80.
4-Quinolone antibiotics: positive genotoxic screening tests
despite an apparent lack of mutation induction.
Bredberg A1, Brant M, Riesbeck K, Azou Y, Forsgren A.
Author information
1Department of Medical Microbiology, University of Lund, Malmö,
Sweden.
Abstract
http://www.ncbi.nlm.nih.gov/pubmed/23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Cioffi%20F%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Senese%20R%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Lanni%20A%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed?term=Goglia%20F%5BAuthor%5D&cauthor=true&cauthor_uid=23769708http://www.ncbi.nlm.nih.gov/pubmed/23769708http://www.ncbi.nlm.nih.gov/pubmed/2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Bredberg%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Brant%20M%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Riesbeck%20K%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Azou%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2921999http://www.ncbi.nlm.nih.gov/pubmed/2921999
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References 4 website: JMR, http://fluoroquinolonethyroid.com
The effects of different 4-quinolone antibiotic derivatives
(4-Qs) in a number of short-term tests commonly employed for the
evaluation of genetic toxicity were studied. Incorporation of
[3H]thymidine into mitogen-stimulated peripheral blood lymphocytes
was strongly enhanced at a low concentration (1.56 micrograms/ml)
for most of the tested 4-Qs, whereas DNA strand breakage in
lymphoblastoid cells was evident only for ciprofloxacin (10
micrograms/ml and upwards), ofloxacin (80 micrograms/ml) and
norfloxacin (160 micrograms/ml). Ciprofloxacin induced a
significant amount of unscheduled DNA synthesis, but was found to
be negative in a shuttle vector plasmid mutation test.
Ciprofloxacin (80 micrograms/ml) did not inhibit enzymes involved
in the early steps of pyrimidine biosynthesis. Cell growth was
slightly depressed at a concentration of 20 micrograms/ml, becoming
marked at 80 micrograms/ml. In conclusion, this study seeks to
contribute to an improved evaluation of genotoxic screening test
data, by focusing attention on the conflicting effects imposed by
the 4-Qs on a battery of such tests.
)From Wiki: A mitogen is a chemical substance that encourages a
cell to commence cell division, triggering
mitosis. A mitogen is usually some form of a protein.
Mitogenesis is the induction (triggering) of mitosis, typically
via a mitogen. Mitogens trigger signal transduction pathways in
which mitogen-activated protein kinase (MAPK) is
involved, leading to mitosis. B cells can enter mitosis when
they encounter an antigen matching their
immunoglobulin. Mitogens are often used to stimulate lymphocytes
and therefore assess immune function.
Lipopolysaccharide toxin from gram-negative bacteria is
thymus-independent. They may directly activate B cells,
regardless of their antigenic specificity. Plasma cells are
terminally differentiated and, therefore, cannot undergo
mitosis. Memory B cells can proliferate to produce more memory
cells or plasma B cells. This is how the mitogen
works, that is, by inducing mitosis in memory B cells to cause
them to divide, with some becoming plasma cells.
Mitogen-activated protein kinases (MAPK) are protein kinases
that are specific to the amino acids, serine,
threonine, and tyrosine.)
Antimicrob Agents Chemother. 1987 May;31(5):774-9.
Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide
biosynthesis and cell growth.
Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF.
Abstract
Several of the new 4-quinolones significantly increase the
incorporation of [3H]thymidine into the DNA of mitogen-stimulated
human lymphocytes. This study suggests that ciprofloxacin inhibits
de novo pyrimidine biosynthesis, thereby resulting in a
compensatory increase in the uptake of pyrimidine precursors
through salvage pathways, and that additional effects may affect
eucaryotic cell growth. Incorporation of deoxyuridine, uridine, and
orotic acid as well as thymidine was increased in the presence of
ciprofloxacin, one of the antibacterially most active of the new
4-quinolones. In contrast, the uptake was decreased in very high
concentrations of the drug. Culture in HAT (hypoxanthine,
aminopterine, thymidine) medium, which blocks de novo thymidylate
synthesis, abrogated the increase in [3H]thymidine incorporation
induced by ciprofloxacin. Ciprofloxacin also failed to increase the
uptake of [14C]hypoxanthine or leucine, indicating a selective
effect on pyrimidine and not on purine nucleotide biosynthesis.
N-(Phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine
nucleotide biosynthesis, also increased [3H]thymidine incorporation
in phytohemagglutinin-stimulated lymphocytes in a fashion similar
to ciprofloxacin. The growth of several cell lines was partially
inhibited by ciprofloxacin at 20 micrograms/ml and completely
inhibited at 80 to 160 micrograms/ml. Growth inhibition by
ciprofloxacin could not be restored by the addition of uridine to
the medium. Chromosome breaks, gene amplification, or other genetic
alterations could not be detected in human lymphocytes incubated
with up to 25 micrograms of ciprofloxacin per ml.
Antimicrob Agents Chemother. 1987 May;31(5):768-73.
http://en.wikipedia.org/wiki/Chemical_substancehttp://en.wikipedia.org/wiki/Cell_divisionhttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Signal_transductionhttp://en.wikipedia.org/wiki/Mitogen-activated_protein_kinasehttp://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Antibodyhttp://en.wikipedia.org/wiki/Lymphocytehttp://en.wikipedia.org/wiki/Lipopolysaccharidehttp://en.wikipedia.org/wiki/Toxinhttp://en.wikipedia.org/wiki/Gram-negative_bacteriahttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Specificity_(tests)http://en.wikipedia.org/wiki/Plasma_cellhttp://en.wikipedia.org/wiki/Cellular_differentiationhttp://en.wikipedia.org/wiki/Memory_B_cellhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Kinasehttp://en.wikipedia.org/wiki/Amino_acidshttp://www.ncbi.nlm.nih.gov/pubmed/3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Bredberg%20A%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Pardee%20AB%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Schlossman%20SF%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed?term=Tedder%20TF%5BAuthor%5D&cauthor=true&cauthor_uid=3606077http://www.ncbi.nlm.nih.gov/pubmed/3606076
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References 4 website: JMR, http://fluoroquinolonethyroid.com
4-Quinolone drugs affect cell cycle progression and function of
human lymphocytes in vitro.
Forsgren A, Schlossman SF, Tedder TF.
Abstract
Most antibacterial agents do not affect human lymphocyte
function, but a few are inhibitory. In contrast, a pronounced
increase in the incorporation of [3H]thymidine in the presence of
4-quinolones was observed in these studies. The uptake of
[3H]thymidine into DNA (trichloroacetic acid precipitable) was
significantly increased in phytohemagglutinin-stimulated human
lymphocytes when they were exposed to eight new 4-quinolone
derivatives, ciprofloxacin, norfloxacin, ofloxacin, A-56619,
A-56620, amifloxacin, enoxacin, and pefloxacin, at 1.6 to 6.25
micrograms/ml for 5 days. Four less antibacterially active
4-quinolones (nalidixic acid, cinoxacin, flumequine, and pipemidic
acid) stimulated [3H]thymidine incorporation only at higher
concentrations or not at all. Kinetic studies showed that
incorporation of [3H]thymidine was not affected or slightly
inhibited by ciprofloxacin 2 days after phytohemagglutinin
stimulation but was increased on days 3 to 6. The total
incorporation of [3H]thymidine from day 1 to day 6 after
phytohemagglutinin stimulation was increased by 42 to 45% at 5 to
20 micrograms of ciprofloxacin per ml. Increased [3H]thymidine
incorporation was also seen when human lymphocytes were stimulated
with mitogens other than phytohemagglutinin. Ciprofloxacin added at
the start of the culture had a more pronounced effect on
[3H]thymidine incorporation than when added later. In spite of the
apparent increase in DNA synthesis, lymphocyte growth was inhibited
by 20 micrograms of ciprofloxacin per ml, and cell cycle analysis
showed that ciprofloxacin inhibited progression through the cell
cycle. In addition, immunoglobulin secretion by human lymphocytes
stimulated by pokeweed mitogen for Epstein-Barr virus was inhibited
by approximately 50% at 5 micrograms of ciprofloxacin per ml. These
results suggest that the 4-quinolone drugs may also affect
eucaryotic cell function in vitro, but additional studies are
needed to establish an in vivo relevance.
(Note: are there increased thymidines in mitochondria, thereby
leading to mutations and cell death?)
Scand J Infect Dis Suppl. 1989;60:39-45.
Effect of ciprofloxacin on human lymphocytes--laboratory studies
(Wow, talk about a turnaround and retraction of his previous
studies . . . ).
Forsgren A1, Bredberg A, Riesbeck K.
Author information
1Department of Medical Microbiology, University of Lund, Malmö
General Hospital, Sweden.
Abstract
4-Quinolones affect mammalian cellular functions in vitro in
several ways. Inhibition of cell proliferation differ widely among
4-quinolones. Ciprofloxacin is one of the most antiproliferative
inhibiting cell growth with about 30% at 20 mg/l. Genotoxicity
tests with 4-quinolones are probably "false" positive due to an
increased [3H]-thymidine uptake not related to DNA damage.
Ciprofloxacin at 10 mg/l and up causes significant DNA strand
breaks which seemingly are quickly repaired and not causing
mutations or cancerogenesis. Ciprofloxacin at 5 mg/l inhibits
immunoglobulin production but the growth factor interleukin 2
(IL-2) is increased by 4-quinolones at the same concentration and
hyperinduced at higher
http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=3606076http://www.ncbi.nlm.nih.gov/pubmed?term=Schlossman%20SF%5BAuthor%5D&cauthor=true&cauthor_uid=3606076http://www.ncbi.nlm.nih.gov/pubmed?term=Tedder%20TF%5BAuthor%5D&cauthor=true&cauthor_uid=3606076http://www.ncbi.nlm.nih.gov/pubmed/2667107http://www.ncbi.nlm.nih.gov/pubmed?term=Forsgren%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2667107http://www.ncbi.nlm.nih.gov/pubmed?term=Bredberg%20A%5BAuthor%5D&cauthor=true&cauthor_uid=2667107http://www.ncbi.nlm.nih.gov/pubmed?term=Riesbeck%20K%5BAuthor%5D&cauthor=true&cauthor_uid=2667107http://www.ncbi.nlm.nih.gov/pubmed/2667107
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References 4 website: JMR, http://fluoroquinolonethyroid.com
concentrations. Thus the effects are very contradictory.
Increased IL-2 may contribute to CNS side effects.
Drug Saf. 1992 May-Jun;7(3):214-22.
Mutagenicity of quinolone antibacterials.
Fort FL.
Author information
Department of Toxicology, Abbott Laboratories, Abbott Park,
Illinois.
Abstract
The literature is summarised on the activity of quinolone
antibacterial compounds in assays which are commonly used for risk
assessment of new pharmaceuticals. These include assays for DNA
damage, sister chromatid exchanges, chromosome aberrations and
mutation induction. The general pattern of activity exhibited by
these compounds is induction of DNA damage in both prokaryotic and
eukaryotic cells, and induction of mutations in DNA
repair-proficient bacteria and at the thymidine kinase locus in
mammalian cells. They do not appear as a class to induce mutations
at the hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) or
Na+,K(+)-ATPase loci or to cause chromosome aberrations. It is
suggested that these actions may be the result of interference with
eukaryotic topoisomerase and that this interference differs in some
respects from the topoisomerase interference caused by certain
antitumour compounds. The postulated mechanism of action has
important implications for assessment of risk from consumption of
quinolone antibacterials. The risk of adverse genotoxic events
should vary directly with the concentration of drug reaching the
intracellular enzyme target and the affinity of the drug for the
target. Results of carcinogenicity studies conducted to date with
the quinolone antibacterials suggest minimal risk from long term
consumption of the newer, second-generation compounds.
Links: Mitochondria, Thyroid, FQ’s,
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC171543/
Ciprofloxacin Does Not Inhibit Mitochondrial
Functions but Other Antibiotics Do
http://www.ncbi.nlm.nih.gov/pubmed/1503668http://www.ncbi.nlm.nih.gov/pubmed?term=Fort%20FL%5BAuthor%5D&cauthor=true&cauthor_uid=1503668http://www.ncbi.nlm.nih.gov/pubmed/1503668http://www.ncbi.nlm.nih.gov/pmc/articles/PMC171543/
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References 4 website: JMR, http://fluoroquinolonethyroid.com
http://www.ncbi.nlm.nih.gov/pubmed/6257866 Influence of diet
composition on serum
triiodothyronine (T3) concentration, hepatic mitochondrial
metabolism and shuttle system activity in
rats
http://www.jbc.org/content/277/18/15225.full Active Site
Mutation in DNA Polymerase γ Associated
with Progressive External Ophthalmoplegia Causes Error-prone DNA
Synthesis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760005/
Bactericidal Antibiotics Induce Mitochondrial
Dysfunction and Oxidative Damage in Mammalian Cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271032/ Inherited
Mitochondrial Diseases of DNA
Replication
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235551/
Mitochondrial Medicine for Aging and
Neurodegenerative Diseases
http://aac.asm.org/content/56/8/4046.full Adverse Effects of
Antimicrobials via Predictable or
Idiosyncratic Inhibition of Host Mitochondrial Components
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041094
Mitochondrial
Topoisomerase I is Critical for Mitochondrial Integrity and
Cellular Energy Metabolism
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175594/
Mitochondrial Biogenesis and Turnover
http://3dmoleculardesigns.com/3DMD-Files/2GoodsellMitochondria.pdf
Miniseries: Illustrating the
Machinery of Life: Mitochondrion
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778844/ A
mitochondrial protein compendium
elucidates complex I disease biology
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219168/ Effect of
3,5-di-iodo-L-thyronine on the
mitochondrial energy-transduction apparatus
http://ajpcell.physiology.org/content/302/2/C463.long
Triiodothyronine induces UCP-1 expression and
mitochondrial biogenesis in human adipocytes
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC209375/ Effect of
triiodothyronine on mitochondrial
energy coupling in human skeletal muscle
http://www.jbc.org/content/239/9/3062.full.pdf Action and
Metabolism of Thyroid Hormones and Iodine-Donating Substances: Site
of Action in the Respiratory Chain. “ We now show that when
electron transport associated with cytochrome b is prevented, an
effect of thyroxine on mitochondria is also blocked. From these
data we may conclude that electron transport in this region is
essential for the action of thyroxine, I2 and ICN.”
http://www.ncbi.nlm.nih.gov/pubmed/6257866http://www.jbc.org/content/277/18/15225.fullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760005/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271032/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235551/http://aac.asm.org/content/56/8/4046.fullhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041094http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175594/http://3dmoleculardesigns.com/3DMD-Files/2GoodsellMitochondria.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778844/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1219168/http://ajpcell.physiology.org/content/302/2/C463.longhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC209375/http://www.jbc.org/content/239/9/3062.full.pdf
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References 4 website: JMR, http://fluoroquinolonethyroid.com
(Need to Google This Title for Link): Thyroid
Economy—Regulation, Cell Biology, Thyroid Hormone
Metabolism and Action: The Special Edition: Metabolic Effects of
Thyroid Hormones Thyroid Hormone
Effects on Mitochondrial Energetics, Mary-Ellen Harper and Erin
L. Seifert
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1186541/ The
Influence of Thyroxine Administered in
vivo on the Transmembrane Protonic Electrochemical Potential
Difference in Rat Liver Mitochondria
http://link.springer.com/article/10.1007%2FBF01458354#page-1
Effects of Iodine upon the Structure
and Function of Mitochondria. This is an excellent paper; I’m
not sure where I got the paper, but it
should be on the internet somewhere. A must read for anyone
interested in iodine and thyroxine
mechanisms of action. Look up author for her other papers as
well. Conclusions were the following:
“The similarity between the effects of iodine compounds and the
thyroxine observed in vivo and in vitro
gives us reason to suggest that: 1. De-iodination of the thyroid
hormone constitutes a necessary step in
the realization of its effect upon the structure and function of
mitochondria. 2. The active components
in the molecule of the thyroid hormone, as regards its
biochemical effect, are the iodine atoms. 3. The
possible places of interaction between the membrane and the
iodine ions (I +) are the negative charges
fixed in the membrane. 4. Neutralization of the charges of the
mitochondrial membrane is the major
event leading to changes in its resistance, conductivity,
permeability and coupling mechanisms of the
oxidative phosphorylation”.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1931645/pdf/amjpathol00388-0058.pdf
STUDIES ON
MITOCHONDRIA: T