Mitochondrial Dynamics: Mechanisms and Pathologies

Abstract

Mitochondrial dynamics, a cellular process describing continuous change of shape and location of mitochondria, has drawn much attention recently due to its involvement in cell injury and human pathologies. Mitochondrial fission and fusion are the major processes that alter mitochondrial morphology. Molecular machineries for mitochondrial fission and fusion include proteins of dynamin family large GTPases that remodel biological membranes. Mutations in these proteins cause hereditary diseases or death in human, indicating that mitochondrial fission and fusion are important cellular processes. Identification of additional factors participating in mitochondrial fission and fusion still continues. Recent studies demonstrate that mitochondrial fission/fusion process is under tight regulation through cellular signalling networks and functional states of mitochondria. This information suggests that cellular cues both extrinsic and intrinsic to mitochondria regulate mitochondrial fission and fusion, indicating an important role of mitochondrial fission and fusion in controlling mitochondrial functionality. Many additional pathologies are associated with aberrant mitochondrial fission and fusion, and defining the form–function relationship of mitochondria will be the key for understanding disease aetiology and therapeutic application.

Key Concepts:

  • Mitochondria take a variety of shapes depending on cell types and activities.

  • Fission and fusion of mitochondria are the main processes changing their morphology.

  • Dynamin‐related proteins (DRPs) remodel mitochondrial membranes for fission and fusion.

  • Additional proteins and factors including signal‐induced protein modifications participate in mitochondrial fission and fusion.

  • Mutations in genes in mitochondrial fission and fusion are detrimental to human health.

  • Many diseases such as neurodegeneration, metabolic diseases, ischemia‐reperfusion injury, heart diseases, and aging are directly and indirectly associated with dysregulation of mitochondrial fission and fusion.

Keywords: mitochondria; mitochondrial dynamics; fission; fusion; dynamin; dynamin‐related proteins; apoptosis; pathology; neurodegeneration

Figure 1.

Mitochondrial morphology in Clone 9, a cell line derived from rat liver (a), and in rat cardiomyocyte (b, c). Filamentous tubules are the major mitochondrial morphology in cultured cell line. Inset in (a) shows elongated tubular mitochondria in cultured cells. On the other hand, both light (b) and electron (c) micrographs show globular mitochondria tightly packed along the myofibrils in cardiomyocytes.

Figure 2.

Molecular structure of DRPs. The dynamin core domains GTPase, Middle, and GED are found in DLP1 and OPA1 whereas the presence of the Middle domain and GED is unclear in Mfn1 and 2. Arrowheads in the OPA1 indicate proteolytic cleavage sites. DLP1, dynamin‐like protein 1; Mfn1/2, mitofusin 1 and 2; OPA1, optic atrophy1; PHD, pleckstrin homology domain; GED, GTPase effector domain; PRD, proline‐rich domain; HR1, heptad‐repeat 1; HR2, heptad‐repeat 2; TM, transmembrane; MTS, mitochondrial targeting sequence; CC, coiled coil domain; MPP, mitochondrial processing peptidase.

Figure 3.

Mitochondrial fission. The ER is suggested to mark the fission site where DLP1 forms helical rings for GTP hydrolysis‐mediated scission of the mitochondrial tubule. DLP1 translocation from the cytosol to the mitochondrial surface is facilitated by Mff, Fis1, or MIEF1 (MiD49/51).

Figure 4.

Mitochondrial fusion. Mfn tethers and fuses the outer membranes (OMM) of adjacent mitochondria. Following the OMM fusion, OPA1 mediates fusion of the inner membranes (IMM).

close

References

Autret A and Martin SJ (2009) Emerging role for members of the Bcl‐2 family in mitochondrial morphogenesis. Molecular Cell 36: 355–363.

Ban T, Heymann JA, Song Z, Hinshaw JE and Chan DC (2010) OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin‐stimulated GTP hydrolysis and membrane tubulation. Human Molecular Genetics 19: 2113–2122.

Berman SB, Chen YB, Qi B et al. (2009) Bcl‐x L increases mitochondrial fission, fusion, and biomass in neurons. Journal of Cell Biology 184: 707–719.

Braschi E, Zunino R and McBride HM (2009) MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Report 10: 748–754.

Cereghetti GM, Stangherlin A, Martins de Brito O et al. (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proceedings of the National Academy of Sciences of the USA 105: 15803–15808.

Chang CR and Blackstone C (2007) Cyclic AMP‐dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. Journal of Biological Chemistry 282: 21583–21587.

Cho DH, Nakamura T, Fang J et al. (2009) S‐nitrosylation of Drp1 mediates beta‐amyloid‐related mitochondrial fission and neuronal injury. Science 324: 102–105.

Cribbs JT and Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP‐dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Report 8: 939–944.

Cui M, Tang X, Christian WV, Yoon Y and Tieu K (2010) Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi‐1. Journal of Biological Chemistry 285: 11740–11752.

DeVay RM, Dominguez‐Ramirez L, Lackner LL et al. (2009) Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. Journal of Cell Biology 186: 793–803.

Eura Y, Ishihara N, Yokota S and Mihara K (2003) Two mitofusin proteins, mammalian homologues of FZO, with distinct functions are both required for mitochondrial fusion. Journal of Biochemistry 134: 333–344.

Frank S, Gaume B, Bergmann‐Leitner ES et al. (2001) The role of dynamin‐related protein 1, a mediator of mitochondrial fission, in apoptosis. Developmental Cell 1: 515–525.

Friedman JR, Lackner LL, West M et al. (2011) ER tubules mark sites of mitochondrial division. Science 334: 358–362.

Gegg ME, Cooper JM, Chau KY et al. (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin‐dependent manner upon induction of mitophagy. Human Molecular Genetics 19: 4861–4870.

Gomes LC, Di Benedetto G and Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nature Cell Biology 13: 589–598.

Griffin EE, Graumann J and Chan DC (2005) The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria. Journal of Cell Biology 170: 237–248.

Han XJ, Lu YF, Li SA et al. (2008) CaM kinase I alpha‐induced phosphorylation of Drp1 regulates mitochondrial morphology. Journal of Cell Biology 182: 573–585.

Head B, Griparic L, Amiri M, Gandre‐Babbe S and van der Bliek AM (2009) Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. Journal of Cell Biology 187: 959–966.

Hinshaw JE (2000) Dynamin and its role in membrane fission. Annual Review of Cell and Developmental Biology 16: 483–519.

Hinshaw JE and Schmid SL (1995) Dynamin self‐assembles into rings suggesting a mechanism for coated vesicle budding. Nature 374: 190–192.

Hoppins S, Edlich F, Cleland MM et al. (2011) The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes. Molecular Cell 41: 150–160.

Ingerman E, Perkins EM, Marino M et al. (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. Journal of Cell Biology 170: 1021–1027.

Ishihara N, Eura Y and Mihara K (2004) Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. Journal of Cell Science 117: 6535–6546.

Ishihara N, Fujita Y, Oka T and Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO Journal 25: 2966–2977.

Ishihara N, Nomura M, Jofuku A et al. (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nature Cell Biology 11: 958–966.

Karbowski M, Lee YJ, Gaume B et al. (2002) Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. Journal of Cell Biology 159: 931–938.

Karbowski M, Neutzner A and Youle RJ (2007) The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. Journal of Cell Biology 178: 71–84.

Karbowski M, Norris KL, Cleland MM, Jeong SY and Youle RJ (2006) Role of Bax and Bak in mitochondrial morphogenesis. Nature 443: 658–662.

Kashatus DF, Lim KH, Brady DC et al. (2011) RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature Cell Biology 13: 1108–1115.

Kim H, Scimia MC, Wilkinson D et al. (2011) Fine‐tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Molecular Cell 44: 532–544.

Koenig J and Ikeda K (1996) Synaptic vesicles have two distinct recycling pathways. Journal of Cell Biology 135: 797–808.

Koshiba T, Detmer SA, Kaiser JT et al. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305: 858–862.

Legesse‐Miller A, Massol RH and Kirchhausen T (2003) Constriction and Dnm1p recruitment are distinct processes in mitochondrial fission. Molecular Biology of the Cell 14: 1953–1963.

McNiven MA, Cao H, Pitts KR and Yoon Y (2000) The dynamin family of mechanoenzymes: pinching in new places. Trends in Biochemical Sciences 25: 115–120.

Mears JA, Lackner LL, Fang S et al. (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nature Structural & Molecular Biology 18: 20–26.

Meeusen S, McCaffery JM and Nunnari J (2004) Mitochondrial fusion intermediates revealed in vitro. Science 305: 1747–1752.

Montessuit S, Somasekharan SP, Terrones O et al. (2010) Membrane remodeling induced by the dynamin‐related protein Drp1 stimulates Bax oligomerization. Cell 142: 889–901.

Mozdy AD, McCaffery JM and Shaw JM (2000) Dnm1p GTPase‐mediated mitochondrial fission is a multi‐step process requiring the novel integral membrane component Fis1p. Journal of Cell Biology 151: 367–380.

Nakamura N, Kimura Y, Tokuda M, Honda S and Hirose S (2006) MARCH‐V is a novel mitofusin 2‐ and Drp1‐binding protein able to change mitochondrial morphology. EMBO Report 7: 1019–1022.

Otera H, Wang C, Cleland MM et al. (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. Journal of Cell Biology 191: 1141–1158.

Palmer CS, Osellame LD, Laine D et al. (2011) MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Report 12: 565–573.

Parone PA, James DI, Da Cruz S et al. (2006) Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak‐dependent apoptosis. Molecular and Cellular Biology 26: 7397–7408.

Praefcke GJ and McMahon HT (2004) The dynamin superfamily: universal membrane tubulation and fission molecules? Nature Reviews Molecular Cell Biology 5: 133–147.

Santel A, Frank S, Gaume B et al. (2003) Mitofusin‐1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. Journal of Cell Science 116: 2763–2774.

Shirendeb U, Reddy AP, Manczak M et al. (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Human Molecular Genetics 20: 1438–1455.

Smirnova E, Griparic L, Shurland DL and van der Bliek AM (2001) Dynamin‐related protein Drp1 is required for mitochondrial division in mammalian cells. Molecular Biology of the Cell 12: 2245–2256.

Song W, Chen J, Petrilli A et al. (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin‐related protein‐1 and increases its enzymatic activity. Nature Medicine 17: 377–382.

Sweitzer SM and Hinshaw JE (1998) Dynamin undergoes a GTP‐dependent conformational change causing vesiculation. Cell 93: 1021–1029.

Taguchi N, Ishihara N, Jofuku A, Oka T and Mihara K (2007) Mitotic phosphorylation of dynamin‐related GTPase Drp1 participates in mitochondrial fission. Journal of Biological Chemistry 282: 11521–11529.

Takei K, McPherson PS, Schmid SL and De Camilli P (1995) Tubular membrane invaginations coated by dynamin rings are induced by GTP‐γS in nerve terminals. Nature 374: 186–190.

Tieu Q and Nunnari J (2000) Mdv1p is a WD repeat protein that interacts with the dynamin‐related GTPase, Dnm1p, to trigger mitochondrial division. Journal of Cell Biology 151: 353–366.

Tieu Q, Okreglak V, Naylor K and Nunnari J (2002) The WD repeat protein, Mdv1p, functions as a molecular adaptor by interacting with Dnm1p and Fis1p during mitochondrial fission. Journal of Cell Biology 158: 445–452.

Tondera D, Santel A, Schwarzer R et al. (2004) Knockdown of MTP18, a novel phosphatidylinositol 3‐kinase‐dependent protein, affects mitochondrial morphology and induces apoptosis. Journal of Biological Chemistry 279: 31544–31555.

Twig G, Elorza A, Molina AJ et al. (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO Journal 27: 433–446.

Wang H, Song P, Du L et al. (2011a) Parkin ubiquitinates Drp1 for proteasome‐dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. Journal of Biological Chemistry 286: 11649–11658.

Wang X, Winter D, Ashrafi G et al. (2011b) PINK1 and parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147: 893–906.

Wasiak S, Zunino R and McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. Journal of Cell Biology 177: 439–450.

Waterham HR, Koster J, van Roermund CW et al. (2007) A lethal defect of mitochondrial and peroxisomal fission. New England Journal of Medicine 356: 1736–1741.

Yonashiro R, Ishido S, Kyo S et al. (2006) A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. EMBO Journal 25: 3618–3626.

Yoon Y, Pitts KR and McNiven MA (2001) Mammalian dynamin‐like protein DLP1 tubulates membranes. Molecular Biology of the Cell 12: 2894–2905.

Yu T, Jhun BS and Yoon Y (2011) High‐glucose stimulation increases reactive oxygen species production through the calcium and mitogen‐activated protein kinase‐mediated activation of mitochondrial fission. Antioxidants & Redox Signaling 14: 425–437.

Zhao J, Liu T, Jin S et al. (2011) Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. EMBO Journal 30: 2762–2778.

Further Reading

Chen H and Chan DC (2009) Mitochondrial dynamics‐‐fusion, fission, movement, and mitophagy‐‐in neurodegenerative diseases. Human Molecular Genetics 18: R169–R176.

Landes T, Leroy I, Bertholet A et al. (2010) OPA1 (dys)functions. Seminars in Cell & Developmental Biology 21: 593–598.

Liesa M, Palacin M and Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiological Reviews 89: 799–845.

Martinou J‐C and Youle RJ (2011) Mitochondria in apoptosis: Bcl‐2 family members and mitochondrial dynamics. Developmental Cell 21: 92–101.

Ong SB and Gustafsson AB (2011) New roles for mitochondria in cell death in the reperfused myocardium. Cardiovascular Research [Epub ahead of print] doi: 10.1093/cvr/cvr312.

Palmer CS, Osellame LD, Stojanovski D and Ryan MT (2011) The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. Cellular Signalling 23: 1534–1545.

Reddy PH and Reddy TP (2011) Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Current Alzheimer Research 8: 393–409.

Schon EA and Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70: 1033–1053.

Yoon Y, Galloway CA, Jhun BS and Yu T (2011) Mitochondrial dynamics in diabetes. Antioxidants & Redox Signaling 14: 439–457.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lee, Hakjoo, and Yoon, Yisang(Jun 2012) Mitochondrial Dynamics: Mechanisms and Pathologies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021867]