Mitochondrial Fission/Fusion and Disease

Abstract

The mitochondria are a multifaceted organelle, central to the function of all eukaryotic cells. Mitochondria are critical to cell metabolism and critical for regulation of intrinsic cell death pathways. This balance between life and death is reliant on the process of mitochondrial fission and fusion, constantly joining and separating to maintain the mitochondrial network within the cell and to facilitate cellular events such as mitosis, biogenesis and maintenance of mitochondrial integrity via mitophagy. The dynamic fluctuations in the architecture of these organelles is garnering increased attention across a broad range of disciplines and diseases. Such diseases include genetic disorders such as Charcot‐Marie‐Tooth disease type 2A and autosomal‐dominant optic atrophy, as well as pathologies associated with mitochondrial dysfunction such as chronic neurodegeneration such as Parkinson disease, type 2 diabetes and various forms of chronic and acute kidney injury.

Key Concepts

  • Mitochondria undergo constant fission and fusion to maintain function and biogenesis.
  • Impairment of mitochondrial dynamics can result in reduced oxidative phosphorylation and cell death.
  • Impairment of mitochondrial dynamics is associated with diseases involving cells abundant in mitochondria.
  • Mitochondrial fusion is associated with energy production.
  • Mitochondrial fragmentation is associated with mitochondrial dysfunction and turnover by mitophagy.

Keywords: mitochondria; fission; fusion; kidney disease; neurodegeneration; cardiovascular disease; cancer

Figure 1. Mitochondrial fission. (a) Drp1 translocates from cytosol to mitochondria to initiate the fission process; (b) Drp1 interacts with MiD49/51, Mff and/or Fis1 to form a ring around the mitochondria to pinch the organelle in half; (c) Fragmented mitochondria separate.
Figure 2. Mitochondrial fusion. (a) Fragmented mitochondria come together through interaction of Opa1 on the inner mitochondrial membrane and Mfn1/2 on the outer mitochondrial membrane; (b) Once the adjacent mitochondria become tethered, the outer mitochondrial membranes fuse together to form a new elongated mitochondria; (c) Mitochondrial fusion is impaired when long isoforms of Opa1 (L‐Opa1) are cleaved (black arrows) into short isoforms of Opa1 (S‐Opa1) by Oma1 and YME1L in the inner mitochondrial membrane or Romo1, which is stimulated by ROS within the mitochondrial matrix.
close

References

Anand R, Wai T, Baker MJ, et al. (2014) The i‐AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. The Journal of Cell Biology 204 (6): 919–929.

Ashrafian H, Docherty L, Leo V, et al. (2010) A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy. PLoS Genetics 6 (6): e1001000.

Bossy B, Petrilli A, Klinglmayr E, et al. (2010) S‐Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer's disease. Journal of Alzheimer's Disease 20 (Suppl 2): S513–S526.

de Brito OM and Scorrano L (2008) Mitofusin 2: a mitochondria‐shaping protein with signaling roles beyond fusion. Antioxidants & Redox Signaling 10 (3): 621–633.

Brooks C, Wei Q, Cho SG and Dong Z (2009) Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. The Journal of Clinical Investigation 119 (5): 1275–1285.

Bueler H (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Experimental Neurology 218 (2): 235–246.

Chang CR and Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin‐related protein Drp1. Annals of the New York Academy of Sciences 1201: 34–39.

Chen H, Detmer SA, Ewald AJ, et al. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. The Journal of Cell Biology 160 (2): 189–200.

Chen Y, Liu Y and Dorn GW, 2nd (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circulation Research 109 (12): 1327–1331.

Chen L, Liu T, Tran A, et al. (2012) OPA1 mutation and late‐onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. Journal of the American Heart Association 1 (5): e003012.

Cho DH, Nakamura T, Fang J, et al. (2009) S‐nitrosylation of Drp1 mediates beta‐amyloid‐related mitochondrial fission and neuronal injury. Science 324 (5923): 102–105.

Cookson MR (2010) DJ‐1, PINK1, and their effects on mitochondrial pathways. Movement Disorders: Official Journal of the Movement Disorder Society 25 (Suppl 1): S44–S48.

Delettre C, Griffoin JM, Kaplan J, et al. (2001) Mutation spectrum and splicing variants in the OPA1 gene. Human Genetics 109 (6): 584–591.

Dorn GW 2nd (2015) Mitochondrial dynamism and heart disease: changing shape and shaping change. EMBO Molecular Medicine 7 (7): 865–877.

Eiberg H, Kjer B, Kjer P and Rosenberg T (1994) Dominant optic atrophy (OPA1) mapped to chromosome 3q region. I. Linkage analysis. Human Molecular Genetics 3 (6): 977–980.

Galloway CA, Lee H, Nejjar S, et al. (2012) Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress. Diabetes 61 (8): 2093–2104.

Griparic L, Kanazawa T and van der Bliek AM (2007) Regulation of the mitochondrial dynamin‐like protein Opa1 by proteolytic cleavage. The Journal of Cell Biology 178 (5): 757–764.

Hickey FB, Corcoran JB, Griffin B, et al. (2014) IHG‐1 increases mitochondrial fusion and bioenergetic function. Diabetes 63 (12): 4314–4325.

Higa M, Zhou YT, Ravazzola M, et al. (1999) Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proceedings of the National Academy of Sciences of the United States of America 96 (20): 11513–11518.

Higgins GC, Beart PM, Shin YS, et al. (2010) Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury. Journal of Alzheimer's Disease: JAD 20 (Suppl 2): S453–S473.

Hirai K, Aliev G, Nunomura A, et al. (2001) Mitochondrial abnormalities in Alzheimer's disease. The Journal of Neuroscience 21 (9): 3017–3023.

Huang P, Galloway CA and Yoon Y (2011) Control of mitochondrial morphology through differential interactions of mitochondrial fusion and fission proteins. PloS One 6 (5): e20655.

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 (Pt 26): 6535–6546.

Ishihara N, Fujita Y, Oka T and Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. The EMBO Journal 25 (13): 2966–2977.

Jin SM and Youle RJ (2012) PINK1‐ and Parkin‐mediated mitophagy at a glance. Journal of Cell Science 125 (Pt 4): 795–799.

Kashatus DF, Lim KH, Brady DC, et al. (2011) RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature Cell Biology 13 (9): 1108–1115.

Kim EY, Zhang Y, Beketaev I, et al. (2015) SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy. Journal of Molecular and Cellular Cardiology 78: 154–164.

Koshiba T, Detmer SA, Kaiser JT, et al. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305 (5685): 858–862.

Lee Y, Lee HY, Hanna RA and Gustafsson AB (2011) Mitochondrial autophagy by Bnip3 involves Drp1‐mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes. American Journal of Physiology. Heart and Circulatory Physiology 301 (5): H1924–H1931.

Lutz AK, Exner N, Fett ME, et al. (2009) Loss of parkin or PINK1 function increases Drp1‐dependent mitochondrial fragmentation. The Journal of Biological Chemistry 284 (34): 22938–22951.

Maechler P (2002) Mitochondria as the conductor of metabolic signals for insulin exocytosis in pancreatic beta‐cells. Cellular and Molecular Life Sciences 59 (11): 1803–1818.

Manczak M and Reddy PH (2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Human Molecular Genetics 21 (11): 2538–2547.

Men X, Wang H, Li M, et al. (2009) Dynamin‐related protein 1 mediates high glucose induced pancreatic beta cell apoptosis. The International Journal of Biochemistry & Cell Biology 41 (4): 879–890.

Misko AL, Sasaki Y, Tuck E, Milbrandt J and Baloh RH (2012) Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. The Journal of Neuroscience 32 (12): 4145–4155.

Norton M, Ng AC, Baird S, et al. (2014) ROMO1 is an essential redox‐dependent regulator of mitochondrial dynamics. Science Signaling 7 (310): ra10.

Olichon A, Landes T, Arnaune‐Pelloquin L, et al. (2007) Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis. Journal of Cellular Physiology 211 (2): 423–430.

Ong SB, Subrayan S, Lim SY, et al. (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121 (18): 2012–2022.

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. The Journal of Cell Biology 191 (6): 1141–1158.

Palmer CS, Elgass KD, Parton RG, et al. (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. The Journal of Biological Chemistry 288 (38): 27584–27593.

Park KS, Wiederkehr A, Kirkpatrick C, et al. (2008) Selective actions of mitochondrial fission/fusion genes on metabolism‐secretion coupling in insulin‐releasing cells. The Journal of Biological Chemistry 283 (48): 33347–33356.

Pickrell AM and Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron 85 (2): 257–273.

Querfurth HW and LaFerla FM (2010) Alzheimer's disease. The New England Journal of Medicine 362 (4): 329–344.

Shen Q, Yamano K, Head BP, et al. (2014) Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Molecular Biology of the Cell 25 (1): 145–159.

Smirnova E, Shurland DL, Ryazantsev SN and van der Bliek AM (1998) A human dynamin‐related protein controls the distribution of mitochondria. The Journal of Cell Biology 143 (2): 351–358.

Soltoff SP (1986) ATP and the regulation of renal cell function. Annual Review of Physiology 48: 9–31.

Tanaka A, Cleland MM, Xu S, et al. (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. The Journal of Cell Biology 191 (7): 1367–1380.

Wang W, Wang Y, Long J, et al. (2012a) Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metabolism 15 (2): 186–200.

Wang X, Petrie TG, Liu Y, et al. (2012b) Parkinson's disease‐associated DJ‐1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction. Journal of Neurochemistry 121 (5): 830–839.

Wang X, Yan MH, Fujioka H, et al. (2012c) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Human Molecular Genetics 21 (9): 1931–1944.

Xiao X, Hu Y, Quiros PM, et al. (2014) OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury. American Journal of Physiology. Renal Physiology 306 (11): F1318–F1326.

Zuchner S, Mersiyanova IV, Muglia M, et al. (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot‐Marie‐Tooth neuropathy type 2A. Nature Genetics 36 (5): 449–451.

Further Reading

Archer SL (2013) Mitochondrial dynamics – mitochondrial fission and fusion in human diseases. The New England Journal of Medicine 369 (23): 2236–2251.

Chen L, Allison J and Knowlton AA (2014) Mitochondrial dynamics changes in health and genetic diseases. Molecular Biology Reports 41 (11): 7053–7062.

Elgass K, Pakay J, Ryan MT and Palmer CS (2013) Recent advances into the understanding of mitochondrial fission. Biochimica et Biophysica Acta 1833 (3): 150–161.

Higgins GC and Coughlan MT (2014) Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? British Journal of Pharmacology 171 (8): 1917–1942.

Karbowski M and Youle RJ (2011) Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Current Opinion in Cell Biology 23 (4): 476–482.

Richter V, Singh AP, Kvansakul M, Ryan MT and Osellame LD (2015) Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission. Cellular and Molecular Life Sciences 72 (19): 3695–3707.

Song M and Dorn GW, II (2015) Mitoconfusion: noncanonical functioning of dynamism factors in static mitochondria of the heart. Cell Metabolism 21 (2): 195–205.

Yoon Y, Galloway CA, et al. (2011) Mitochondrial dynamics and diabetes. Antioxidant and Redox Signaling 14 (3): 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
Higgins, Gavin C, and Coughlan, Melinda T(Jan 2016) Mitochondrial Fission/Fusion and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021879]