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Snapshot: Mitochondrial Dynamics SnapShot: Mitochondrial Dynamics Yasushi Tamura,1 Kie Itoh,1 and Hiromi Sesaki,1 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Mitochondrial fusion-division cycle Mitochondrial shape Drp1/Dnm1 Fusion < Division Fusion ≈ Division Fusion > Division Drp1/Dnm1 receptor Fragmented Tubular Elongated Mfn1 and 2/Fzo1 Opa1/Mgm1 MEF Yeast Fragmented with 10 µm 5 µm swollen cristae Enlarged Fusion machinery CYTOSOL Mammals CYTOSOL Yeast Positive regulator for Mfn2 Bax Bcl-xL Mfn1 Mfn2 Ubiquitin ligase for Mfn1 and 2 G Proteasome Negative regulator Ub degraded Parkin Pink1 MITOL/March5 Ub for Mfn1 and 2 G R R MIB Mdm30 Ugo1 OM SCF Fzo1 OM G Ubiquitin ligase IMS G for Fzo1 i-AAA s-Opa1 G IMS G IM s-Mgm1 IM Parl l-Opa1 Oma1 m-AAA Pcp1 l-Mgm1 Processing peptidases Processing peptidases HUMAN DISEASE ASSOCIATION for Mgm1 for Opa1 Mfn2: Charcot-Marie-Tooth type 2A Parkin and Pink1: Parkinson’s disease MATRIX Opa1: Autosomal dominant optic atrophy type 1 MATRIX Division machinery Mammals Yeast Algae CYTOSOL Posttranslational CYTOSOL CYTOSOL modulators for Drp1 PKA CaMKla P Calcineurin Cdk1-cyclin B Cortical actin G G NO G G Dnm1 Dnm1 Senp5 Dnm1 Dnm1 Ub SUMO Mda1 G Mdv1 G MAPL Caf4 Drp1 MITOL/March5 Num1 Dnm1 RR Fis1 R Fis1 Mdm36 OM OM OM GDAP1 IMS IMS Drp1 receptors IMS Mff MiD49/MiD51 IM IM ? Fis1 IM ? FtsZ MATRIX ZED G HUMAN DISEASE ASSOCIATION Drp1: Postneonatal death with neurodevelopmental disorders GDAP1: Charcot-Marie-Tooth type 4A MATRIX MATRIX 1158 Cell 145, June 24, 2011 ©2011 Elsevier Inc. DOI 10.1016/j.cell.2011.06.018 See online version for legend and references. SnapShot: Mitochondrial Dynamics Yasushi Tamura,1 Kie Itoh,1 and Hiromi Sesaki,1 1Department 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 morphol- ogy; imbalanced dynamics leads to altered morphology, which is associated with a variety of pathological conditions. When fusion is decreased, mitochondria fragment into small, spherical mitochondria that are often characterized by swollen cristae and impaired respiratory functions. When division is inhibited, tubular mitochondria fuse, generating 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 linked to several neurodevelopmental and neurodegenerative diseases, including a birth defect with multiple neurological disorders (Drp1), Parkinson’s disease (Parkin and Pink1), autosomal dominant optic atrophy type 1 (Opa1), and Charcot-Marie-Tooth neuropathies (Mfn2 and GDAP1). In addition, although Alzheimer’s and Huntington’s diseases are not associated 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 (Mgm1) 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 (Dnm1) is 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), which are regulated by ubiquitin proteasome pathway, influence the amount of organelle fusion. In mammals, mitofusins are ubiquitinated by two E3 ligases, MITOL/March5 and Parkin. MITOL/March5 is located in the outer membrane and ubiquitinates mitofusin 1. Parkin is translocated to dysfunctional, depolarized mitochondria by the Pink1 kinase. Ubiquit- ination and proteasomal degradation of mitofusins inhibit refusion of damaged mitochondria and promote autophagic degradation of mitochondria. The ubiquitin proteasome pathway plays a similar role in yeast, with the ubiquitin ligase SCFMdm30 regulating 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 mito- 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 proteolytic cleavage of the integrated membrane form. Both are required for mitochondrial fusion. In mammals, several inner membrane-localized proteases cleave Opa1, including PARL, i-AAA, 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 (Mgm1) processing. Because mitochondrial have two membranes, efficient fusion of the organelle requires coordination of outer- and inner-membrane fusion. Ugo1, an outer-membrane protein 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 mitochondrial sur- face. 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, GDAP1, 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-dependent 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 functionally 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 corti- cal protein Num1 retain Dnm1 at the mitochondrial surface. The Num1-Mdm36 mechanism connects mitochondria to the cell cortex and promotes appropriate segregation and inheritance 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 bacterial 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. The 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 mem- 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 for the 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, 678–684. 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, 34–39. Chen, H., and Chan, D.C. (2009). Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum. Mol. Genet. 18 (R2), R169–R176. Hoppins, S., and Nunnari, J. (2009). The molecular mechanism of mitochondrial fusion. Biochim. Biophys. Acta 1793, 20–26. 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. 86, 455–471. McBride, H., and Soubannier, V. (2010). Mitochondrial function: OMA1 and OPA1, the grandmasters of mitochondrial health. Curr. Biol. 20, R274–R276. 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. EMBO Rep. 12, 565–573. 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. Biol. 21, 542–549. Youle, R.J., and Narendra, D.P. (2011). Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14. 1158.e1 Cell 145, June 24, 2011 ©2011 Elsevier Inc. DOI 10.1016/j.cell.2011.06.018.
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