-
8/10/2019 Pi is 009286741100660 x
1/2
See online version for legend and references.1158 Cell 145, June 24, 2011 2011 Elsevier Inc. DOI 10.1016/j.cell.2011.06.018
SnapShot: Mitochondrial DynamicsYasushi Tamura,1Kie Itoh,1and Hiromi Sesaki,1
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Mitochondrial fusion-division cycle
Fusion machinery
Mitochondrial shape
Division machinery
Drp1/Dnm1
Drp1/Dnm1 receptor
Mfn1 and 2/Fzo1
Opa1/Mgm1
Elongated
Enlarged
Fragmented
Fragmented withswollen cristae
Fusion < Division Fusion > Division
Tubular
Fusion Division
10 m 5 m
YeastMEF
Ub
ParlOma1
i-AAA
m-AAA
R
l-Opa1
Mfn1Mfn2
MITOL/March5Parkin Pink1
Ubiquitin ligase for Mfn1 and 2
Processing peptidasesfor Opa1
MIB
Negative regulatorfor Mfn1 and 2
I M
M A T R I X
O M
I M S
Mammals
H U M A N D I S E A S E A S S O C I A T I O N
Mfn2:Charcot-Marie-Tooth type 2A
Parkin and Pink1:Parkinsons disease
Opa1:Autosomal dominant optic atrophy type 1
s-Opa1
Bax
Bcl-xL
Positive regulator
for Mfn2
G
G
G
R
Ub
SCF Mdm30 Fzo1 Ugo1
l-Mgm1Pcp1
G
Processing peptidasesfor Mgm1
Ubiquitin ligasefor Fzo1
Proteasomedegraded
Yeast
s-Mgm1
G
G
I M
M A T R I X
OM
I M S
I M
OM
I M S
M A T R I X
GDrp1
PKACaMKla
Cdk1-cyclin B
Calcineurin
SUMO
MAPL
Senp5
GDAP1
Mammals
Drp1:Postneonatal death with neurodevelopmental disorders
GDAP1: Charcot-Marie-Tooth type 4A
Drp1 receptorsMffMiD49/MiD51Fis1
R R R
Ub
NO
P
?
H U M A N D I S E A S E A S S O C I A T I O N
MITOL/March5MITOL/March5
Posttranslationalmodulators for Drp1Posttranslationalmodulators for Drp1
Fis1
Mdv1Caf4
I M
M A T R I X
OM
I M S
?
Yeast
Num1
GDnm1
G GDnm1Dnm1
Mdm36
Cortical actinCortical actin
I M
O M
M A T R I X
I M S
Mda1
GFtsZ
ZED
Algae
Fis1
Dnm1
GDnm1
G
-
8/10/2019 Pi is 009286741100660 x
2/2
1158.e1 Cell 145, June 24, 2011 2011 Elsevier Inc. DOI 10.1016/j.cell.2011.06.018
SnapShot: Mitochondrial DynamicsYasushi Tamura,1Kie Itoh,1and Hiromi Sesaki,1
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Mitochondrial Fusion and Division
Mitochondria are tubular, highly dynamic organelles that continuously fuse and divide in a regulated manner. A balance of fusion and division controls mitochondrial mor
ogy; imbalanced dynamics leads to altered morphology, which is associated with a variety of pathological conditions. When fusion is decreased, mitochondria fragment
small, spherical mitochondria that are often characterized by swollen cristae and impaired respiratory functions. When division is inhibited, tubular mitochondria fuse, gener
elongated mitochondrial tubules with increased connectivity. In some neurons, however, decreased division leads to enlarged, spherical mitochondria.
Highlighting the importance of mitochondrial fusion and division in human health and disease, mutations in mitochondrial dynamics components have recently been lin
to several neurodevelopmental and neurodegenerative diseases, including a birth defect with multiple neurological disorders (Drp1), Parkinsons disease (Parkin and P
autosomal dominant optic atrophy type 1 (Opa1), and Charcot-Marie-Tooth neuropathies (Mfn2 and GDAP1). In addition, although Alzheimers and Huntingtons diseases arassociated with such mutations, they do show altered activity and abundance of mitochondrial dynamics components.
Core Machineries for Mitochondrial Fusion and Division
Dynamin-related GTPases feature prominently in mitochondrial fusion and division. Complexes of mitofusin 1 and 2 (Fzo1) control outer-membrane fusion, whereas Opa1 (M
mediates inner-membrane fusion. In addition to its role in fusion, Opa1 (Mgm1) has been implicated in direct control of cristae junctions. For mitochondrial division, Drp1 (D
s recruited to the organelle surface, where it assembles into spiral filaments that are thought to generate mechanical force, constricting and pinching off the mitochondria.
Regulation of Fusion
Although outer- and inner-membrane fusion events are coordinated, these processes require separate machineries. In the outer membrane, levels of mitofusins (Fzo1), whic
regulated by ubiquitin proteasome pathway, influence the amount of organelle fusion. In mammals, mitofusins are ubiquitinated by two E3 ligases, MITOL/March5 and PaMITOL/March5 is located in the outer membrane and ubiquitinates mitofusin 1. Parkin is translocated to dysfunctional, depolarized mitochondria by the Pink1 kinase. Ubi
nation and proteasomal degradation of mitofusins inhibit refusion of damaged mitochondria and promote autophagic degradation of mitochondria. The ubiquitin proteas
pathway plays a similar role in yeast, with the ubiquitin ligase SCFMdm30regulating the levels of Fzo1.
Mitochondrial fusion can be modulated independently of the amount of fusion proteins. For instance, the proapoptotic Bcl-2 family members Bax and Bcl-xL stimulate m
fusin 2 activity, whereas a mitofusin-binding protein (MIB) inhibits mitofusin 1 and 2.
In the inner membrane, Opa1 (Mgm1) exists in two forms: l-Opa1 (l-Mgm1) is integral to the inner membrane, and s-Opa1 (s-Mgm1) is soluble as a result of p roteolytic cleaof the integrated membrane form. Both are required for mitochondrial fusion. In mammals, several inner membrane-localized proteases cleave Opa1, including PARL, i-A
m-AAA, and Oma1. In yeast, a homolog of PARL, Pcp1, cleaves Mgm1. Changes in matrix ATP levels and the membrane potential across the inner membrane affect Opa1 (Mprocessing.
Because mitochondrial have two membranes, efficient fusion of the organelle requires coordination of outer- and inner-membrane fusion. Ugo1, an outer-membrane pr
binds Fzo1 and Mgm1, linking these two fusion events in yeast. The mammalian homolog of Ugo1 remains unidentified.
Regulation of Division Machinery
Multiple integral outer-membrane proteins recruit Drp1 (Dnm1) to mitochondria. In mammals, Mff and MiD49/51 interact directly with Drp1, anchoring it to the mitochondrialface. Fis1 was the first outer-membrane protein identified as a tether for Drp1, but its function has been challenged recently. One other integral outer-membrane protein, GD
has also been implicated in Drp1-dependent mitochondrial division in mammals; however, the exact function of this protein awaits elucidation.
Several types of posttranslational modifications regulate Drp1 in mammals. Similar to mitofusins, the activity of Drp1 appears to be regulated by MITOL/March5-depen
ubiquitination. In addition, SUMOylation, phosphorylation, and N-nitrosylation of Drp1 also control its functions.
Although Drp1 appears to bind directly to outer-membrane receptors to promote division in mammalian cells, Dnm1 is tethered to the outer membrane by two functio
redundant protein complexes in yeast. Fis1 recruits Dnm1 via two WD40 domain-containing adaptor proteins, Mdv1 and Caf4. Parallel to this mechanism, Mdm36 and the ccal protein Num1 retain Dnm1 at the mitochondrial surface. The Num1-Mdm36 mechanism connects mitochondria to the cell cortex and promotes appropriate segregation
nheritance of mitochondria during cytokinesis.
In algae, Dnm1 is proposed to associate with Fis1 and the WD40 domain-containing protein Mda1 on the outer membrane. Additionally, two proteins related to bact
division components, FtsZ and ZED, are located on the matrix side of the inner membrane and form a ring structure, which potentially mediates inner-membrane division.
machinery necessary for inner-membrane division has yet to be identified in mammals and yeast.
Abbreviations
Mfn, mitofusin; G, GTPase; R, ring-domain; Ub, ubiquitin; P, phosphate; SUMO, small ubiquitin-like modifier; OM, outer membrane; IMS, intermembrane space; IM, inner m
brane; SCF, Skp1-cullin-F box; MEF, mouse embryonic fibroblast. When the names for mammalian and their yeast orthologs differ, the yeast name is in parentheses.
ACKNOWLEDGMENTS
We thank M. Iijima for helpful discussions and Y. Kageyama for providing the image of mitochondria in mouse embryonic fibroblasts. Y.T. is supported by a Japan Society fo
Promotion of Science fellowship. H.S. is supported by a National Institutes of Health grant (GM89853).
REFERENCES
Campello, S., and Scorrano, L. (2010). Mitochondrial shape changes: orchestrating cell pathophysiology. EMBO Rep. 11, 678684.
Chang, C.R., and Blackstone, C. (2010). Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann. N Y Acad. Sci. 1201, 3439
Chen, H., and Chan, D.C. (2009). Mitochondrial dynamicsfusion, fission, movement, and mitophagyin neurodegenerative diseases. Hum. Mol. Genet.18(R2), R169R176.
Hoppins, S., and Nunnari, J. (2009). The molecular mechanism of mitochondrial fusion. Biochim. Biophys. Acta 1793, 2026.
Kageyama, Y., Zhang, Z., and Sesaki, H. (2011). Mitochondrial division: molecular machinery and physiological functions. Curr. Opin. Cell Biol.
Kuroiwa, T. (2010). Mechanisms of organelle division and inheritance and their implications regarding the origin of eukaryotic cells. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci
455471.
McBride, H., and Soubannier, V. (2010). Mitochondrial function: OMA1 and OPA1, the grandmasters of mitochondrial health. Curr. Biol. 20, R274R276.
Palmer, C.S., Osellame, L.D., Laine, D., Koutsopoulos, O.S., Frazier, A.E., and Ryan, M.T. (2011). MiD49 and MiD51, new components of the mitochondrial fission machinery. E
Rep. 12, 565573.
Westermann, B. (2010). Mitochondrial dynamics in model organisms: what yeasts, worms and flies have taught us about fusion and fission of mitochondria. Semin. Cell Dev.
21, 542549.
Youle, R.J., and Narendra, D.P. (2011). Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 914.
