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Mitochondria in heart failure: the emerging role of mitochondrial dynamics

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Abstract

Over the past decade, mitochondria have emerged as critical integrators of energy production, generation of reactive oxygen species (ROS), multiple cell death, and signaling pathways in the constantly beating heart. Clarification of the molecular mechanisms, underlying mitochondrial ROS generation and ROS-induced cell death pathways, associated with cardiovascular diseases, by itself remains an important aim; more recently, mitochondrial dynamics has emerged as an important active mechanism to maintain normal mitochondria number and morphology, both are necessary to preserve cardiomyocytes integrity. The two opposing processes, division (fission) and fusion, determine the cell type-specific mitochondrial morphology, the intracellular distribution and activity. The tightly controlled balance between fusion and fission is of particular importance in the high energy demanding cells, such as cardiomyocytes, skeletal muscles, and neuronal cells. A shift toward fission will lead to mitochondrial fragmentation, observed in quiescent cells, while a shift toward fusion will result in the formation of large mitochondrial networks, found in metabolically active cardiomyocytes. Defects in mitochondrial dynamics have been associated with various human disorders, including heart failure, ischemia reperfusion injury, diabetes, and aging. Despite significant progress in our understanding of the molecular mechanisms of mitochondrial function in the heart, further focused research is needed to translate this knowledge into the development of new therapies for various ailments.

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References

  1. Kane LA, Youle RJ (2010) Mitochondrial fission and fusion and their roles in the heart. J Mol Med (Berl) 88:971–979

    Article  Google Scholar 

  2. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM (2002) Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage. Gene 286:135–141

    Article  PubMed  CAS  Google Scholar 

  3. Ide T, Tsutsui H, Hayashidani S et al (2001) Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 88:529–535

    Article  PubMed  CAS  Google Scholar 

  4. Ide T, Tsutsui H, Kinugawa S et al (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 85:357–363

    Article  PubMed  CAS  Google Scholar 

  5. Giordano FJ (2005) Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 115:500–508

    PubMed  CAS  Google Scholar 

  6. Cesselli D, Jakoniuk I, Barlucchi L et al (2001) Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89:279–286

    Article  PubMed  CAS  Google Scholar 

  7. Marin-Garcia J, Goldenthal MJ, Moe GW (2001) Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc Res 52:103–110

    Article  PubMed  CAS  Google Scholar 

  8. Nordberg J, Arner ES (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31:1287–1312

    Article  PubMed  CAS  Google Scholar 

  9. Nojiri H, Shimizu T, Funakoshi M et al (2006) Oxidative stress causes heart failure with impaired mitochondrial respiration. J Biol Chem 281:33789–33801

    Article  PubMed  CAS  Google Scholar 

  10. Huang TT, Carlson EJ, Kozy HM et al (2001) Genetic modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant mice. Free Radic Biol Med 31:1101–1110

    Article  PubMed  CAS  Google Scholar 

  11. Conrad M, Jakupoglu C, Moreno SG et al (2004) Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol 24:9414–9423

    Article  PubMed  CAS  Google Scholar 

  12. Li Y, Huang TT, Carlson EJ et al (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 11:376–381

    Article  PubMed  CAS  Google Scholar 

  13. Shiomi T, Tsutsui H, Matsusaka H et al (2004) Overexpression of glutathione peroxidase prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 109:544–549

    Article  PubMed  CAS  Google Scholar 

  14. Schriner SE, Linford NJ, Martin GM et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911

    Article  PubMed  CAS  Google Scholar 

  15. Mak S, Newton GE (2001) The oxidative stress hypothesis of congestive heart failure: radical thoughts. Chest 120:2035–2046

    Article  PubMed  CAS  Google Scholar 

  16. Sam F, Kerstetter DL, Pimental DR et al (2005) Increased reactive oxygen species production and functional alterations in antioxidant enzymes in human failing myocardium. J Card Fail 11:473–480

    Article  PubMed  CAS  Google Scholar 

  17. Narula J, Haider N, Virmani R et al (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189

    Article  PubMed  CAS  Google Scholar 

  18. Olivetti G, Abbi R, Quaini F et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141

    Article  PubMed  CAS  Google Scholar 

  19. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  PubMed  CAS  Google Scholar 

  20. Li LY, Luo X, Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95–99

    Article  PubMed  CAS  Google Scholar 

  21. Susin SA, Lorenzo HK, Zamzami N et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446

    Article  PubMed  CAS  Google Scholar 

  22. Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147–157

    Article  PubMed  CAS  Google Scholar 

  23. Kroemer G (2003) Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun 304:433–435

    Article  PubMed  CAS  Google Scholar 

  24. Marzo I, Brenner C, Zamzami N et al (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 187:1261–1271

    Article  PubMed  CAS  Google Scholar 

  25. Scorrano L, Ashiya M, Buttle K et al (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2:55–67

    Article  PubMed  CAS  Google Scholar 

  26. Scorrano L, Oakes SA, Opferman JT et al (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300:135–139

    Article  PubMed  CAS  Google Scholar 

  27. Morishima N, Nakanishi K, Tsuchiya K, Shibata T, Seiwa E (2004) Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. J Biol Chem 279:50375–50381

    Article  PubMed  CAS  Google Scholar 

  28. Neuss M, Monticone R, Lundberg MS, Chesley AT, Fleck E, Crow MT (2001) The apoptotic regulatory protein ARC (apoptosis repressor with caspase recruitment domain) prevents oxidant stress-mediated cell death by preserving mitochondrial function. J Biol Chem 276:33915–33922

    Article  PubMed  CAS  Google Scholar 

  29. Pi Y, Goldenthal MJ, Marin-Garcia J (2007) Mitochondrial involvement in IGF-1 induced protection of cardiomyocytes against hypoxia/reoxygenation injury. Mol Cell Biochem 301:181–189

    Article  PubMed  CAS  Google Scholar 

  30. Marín-García J, Goldenthal MJ (2008) Mitochondrial centrality in heart failure. Heart Fail Rev 13:137–150

    Article  PubMed  Google Scholar 

  31. Kirshenbaum LA, de Moissac D (1997) The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 96:1580–1585

    Article  PubMed  CAS  Google Scholar 

  32. Zhu L, Yu Y, Chua BH, Ho YS, Kuo TH (2001) Regulation of sodium-calcium exchange and mitochondrial energetics by Bcl-2 in the heart of transgenic mice. J Mol Cell Cardiol 33:2135–2144

    Article  PubMed  CAS  Google Scholar 

  33. Kang PM, Haunstetter A, Aoki H, Usheva A, Izumo S (2000) Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ Res 87:118–125

    Article  PubMed  CAS  Google Scholar 

  34. Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y (2000) Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol 150:1283–1298

    Article  PubMed  CAS  Google Scholar 

  35. Linden M, Li Z, Paulin D, Gotow T, Leterrier JF (2001) Effects of desmin gene knockout on mice heart mitochondria. J Bioenerg Biomembr 33:333–341

    Article  PubMed  CAS  Google Scholar 

  36. Weisleder N, Taffet GE, Capetanaki Y (2004) Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. Proc Natl Acad Sci USA 101:769–774

    Article  PubMed  CAS  Google Scholar 

  37. Imahashi K, Schneider MD, Steenbergen C, Murphy E (2004) Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 95:734–741

    Article  PubMed  CAS  Google Scholar 

  38. Vahsen N, Cande C, Briere JJ et al (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689

    Article  PubMed  CAS  Google Scholar 

  39. Joza N, Oudit GY, Brown D et al (2005) Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol Cell Biol 25:10261–10272

    Article  PubMed  CAS  Google Scholar 

  40. Kajstura J, Cheng W, Reiss K et al (1996) Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 74:86–107

    PubMed  CAS  Google Scholar 

  41. Rayment NB, Haven AJ, Madden B et al (1999) Myocyte loss in chronic heart failure. J Pathol 188:213–219

    Article  PubMed  CAS  Google Scholar 

  42. Gill C, Mestril R, Samali A (2002) Losing heart: the role of apoptosis in heart disease—a novel therapeutic target? Faseb J 16:135–146

    Article  PubMed  CAS  Google Scholar 

  43. Honda O, Kuroda M, Joja I et al (2000) Assessment of secondary necrosis of Jurkat cells using a new microscopic system and double staining method with annexin V and propidium iodide. Int J Oncol 16:283–288

    PubMed  CAS  Google Scholar 

  44. Malhi H, Gores GJ, Lemasters JJ (2006) Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43:S31–S44

    Article  PubMed  CAS  Google Scholar 

  45. Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304:463–470

    Article  PubMed  CAS  Google Scholar 

  46. Lemasters JJ, Nieminen AL, Qian T et al (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177–196

    Article  PubMed  CAS  Google Scholar 

  47. Zamzami N, Hirsch T, Dallaporta B, Petit PX, Kroemer G (1997) Mitochondrial implication in accidental and programmed cell death: apoptosis and necrosis. J Bioenerg Biomembr 29:185–193

    Article  PubMed  CAS  Google Scholar 

  48. Nakayama H, Chen X, Baines CP et al (2007) Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest 117:2431–2444

    Article  PubMed  CAS  Google Scholar 

  49. Yoshida K, Hanafusa T, Matoba R, Wakasugi C (1990) Proteolysis of myosin and troponin in human myocardium of elderly subjects. Jpn Heart J 31:683–691

    Article  PubMed  CAS  Google Scholar 

  50. Cuervo AM, Dice JF (2000) Age-related decline in chaperone-mediated autophagy. J Biol Chem 275:31505–31513

    Article  PubMed  CAS  Google Scholar 

  51. Cuervo AM (2004) Autophagy: many paths to the same end. Mol Cell Biochem 263(1–2):55–72

    Article  PubMed  CAS  Google Scholar 

  52. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477

    Article  PubMed  CAS  Google Scholar 

  53. Ohsumi Y, Mizushima N (2004) Two ubiquitin-like conjugation systems essential for autophagy. Semin Cell Dev Biol 15:231–236

    Article  PubMed  CAS  Google Scholar 

  54. Kissova I, Deffieu M, Manon S, Camougrand N (2004) Uth1p is involved in the autophagic degradation of mitochondria. J Biol Chem 279:39068–39074

    Article  PubMed  CAS  Google Scholar 

  55. Lemasters JJ (2005) Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 8:3–5

    Article  PubMed  CAS  Google Scholar 

  56. Zhu H, Tannous P, Johnstone JL et al (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117:1782–1793

    Article  PubMed  CAS  Google Scholar 

  57. Yan L, Vatner DE, Kim SJ et al (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci USA 102:13807–13812

    Article  PubMed  CAS  Google Scholar 

  58. Takemura G, Miyata S, Kawase Y, Okada H, Maruyama R, Fujiwara H (2006) Autophagic degeneration and death of cardiomyocytes in heart failure. Autophagy 2:212–214

    PubMed  CAS  Google Scholar 

  59. Terman A, Brunk UT (1998) On the degradability and exocytosis of ceroid/lipofuscin in cultured rat cardiac myocytes. Mech Ageing Dev 100:145–156

    Article  PubMed  CAS  Google Scholar 

  60. Grune T, Merker K, Jung T, Sitte N, Davies KJ (2005) Protein oxidation and degradation during postmitotic senescence. Free Radic Biol Med 39:1208–1215

    Article  PubMed  CAS  Google Scholar 

  61. Rooyackers OE, Adey DB, Ades PA, Nair KS (1996) Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proc Natl Acad Sci USA 93:15364–15369

    Article  PubMed  CAS  Google Scholar 

  62. Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269:1996–2002

    Article  PubMed  CAS  Google Scholar 

  63. Terman A, Brunk UT (2005) Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 68(3):355–365

    Article  PubMed  CAS  Google Scholar 

  64. Kurz T, Eaton JW, Brunk UT (2011) The role of lysosomes in iron metabolism and recycling. Int J Biochem Cell Biol 43:1686–1697

    Article  PubMed  CAS  Google Scholar 

  65. Brunk UT, Neuzil J, Eaton JW (2001) Lysosomal involvement in apoptosis. Redox Rep 6:91–97

    Article  PubMed  CAS  Google Scholar 

  66. Terman A, Gustafsson B, Brunk UT (2006) The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 163:29–37

    Article  PubMed  CAS  Google Scholar 

  67. Yan L, Sadoshima J, Vatner DE, Vatner SF (2006) Autophagy: a novel protective mechanism in chronic ischemia. Cell Cycle 5:1175–1177

    Article  PubMed  CAS  Google Scholar 

  68. Kunapuli S, Rosanio S, Schwarz ER (2006) “How do cardiomyocytes die?” apoptosis and autophagic cell death in cardiac myocytes. J Card Fail 12:381–391

    Article  PubMed  CAS  Google Scholar 

  69. Iglewski M, Hill JA, Lavandero S, Rothermel BA (2010) Mitochondrial fission and autophagy in the normal and diseased heart. Curr Hypertens Rep 12:418–425

    Article  PubMed  Google Scholar 

  70. Taneike M, Yamaguchi O, Nakai A et al. (2010) Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6(5):600–606

    Article  PubMed  CAS  Google Scholar 

  71. Nishida K, Otsu K (2008) Cell death in heart failure. Circ J 72(Suppl A):A17–A21

    Google Scholar 

  72. Nakai A, Yamaguchi O, Takeda T et al (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624

    Article  PubMed  CAS  Google Scholar 

  73. Chen H, Chan DC (2009) Mitochondrial dynamics–fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 18(R2):R169–R176

    Google Scholar 

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

    Google Scholar 

  75. Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879

    Article  PubMed  CAS  Google Scholar 

  76. Okamoto K, Shaw JM (2005) Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet 39:503–536

    Article  PubMed  CAS  Google Scholar 

  77. Twig G, Hyde B, Shirihai OS (2008) Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 1777:1092–1097

    Article  PubMed  CAS  Google Scholar 

  78. Chen H, Chen DC (2010) Physiological functions of mitochondrial fusion. Ann NY Acad Sci 1201:21–25

    Article  PubMed  CAS  Google Scholar 

  79. Li J, Zhou J, Li Y, Qin D, Li P (2010) Mitochondrial fission controls DNA fragmentation by regulating endonuclease G. Free Radic Biol Med 49:622–631

    Article  PubMed  CAS  Google Scholar 

  80. Shenouda SM, Widlansky ME, Chen K et al (2011) Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation 124:444–453

    Article  PubMed  CAS  Google Scholar 

  81. Meeusen S, DeVay R, Block J et al (2006) Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127:383–395

    Article  PubMed  CAS  Google Scholar 

  82. Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell 20:3525–3532

    Article  PubMed  CAS  Google Scholar 

  83. Alavi MV, Bette S, Schimpf S et al (2007) A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain 130:1029–1042

    Article  PubMed  Google Scholar 

  84. Davies VJ, Hollins AJ, Piechota MJ et al (2007) Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet 16:1307–1318

    Article  PubMed  CAS  Google Scholar 

  85. Rojo M, Legros F, Chateau D, Lombes A (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 15:1663–1674

    Google Scholar 

  86. Sesaki H, Jensen RE (2001) UGO1 encodes an outer membrane protein required for mitochondrial fusion. J Cell Biol 152:1123–1134

    Article  PubMed  CAS  Google Scholar 

  87. Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192

    Article  PubMed  CAS  Google Scholar 

  88. Amati-Bonneau P, Valentino ML, Reynier P et al (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain 131:338–351

    Article  PubMed  Google Scholar 

  89. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  PubMed  CAS  Google Scholar 

  90. Hudson G, Amati-Bonneau P, Blakely EL et al (2008) Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain 131:329–337

    Article  PubMed  Google Scholar 

  91. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol 15:5001–5011

    CAS  Google Scholar 

  92. Gandre-Babbe S, van der Bliek AM (2008) The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 19:2402–2412

    Article  PubMed  CAS  Google Scholar 

  93. 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. J Cell Biol 191:1141–1158

    Article  PubMed  CAS  Google Scholar 

  94. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884

    Article  PubMed  CAS  Google Scholar 

  95. Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22:1577–1590

    Article  PubMed  CAS  Google Scholar 

  96. Margineantu DH, Gregory CW, Sundell L, Sherwood SW, Beechem JM, Capaldi RA (2002) Cell cycle dependent morphology changes and associated mitochondrial DNA redistribution in mitochondria of human cell lines. Mitochondrion 1:425–435

    Article  PubMed  CAS  Google Scholar 

  97. Chen H, Vermulst M, Wang YE et al (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280–289

    Article  PubMed  CAS  Google Scholar 

  98. Elachouri G, Vidoni S, Zanna C et al (2011) OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res 21:12–20

    Article  PubMed  CAS  Google Scholar 

  99. Zanna C, Ghelli A, Porcelli AM et al (2008) OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 131:352–367

    Article  PubMed  Google Scholar 

  100. Pich S, Bach D, Briones P et al (2005) The charcot-marie-tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 14:1405–1415

    Article  PubMed  CAS  Google Scholar 

  101. Bach D, Pich S, Soriano FX et al (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278:17190–17197

    Article  PubMed  CAS  Google Scholar 

  102. Parone PA, Da CS, Tondera D et al (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3:e3257

    Article  PubMed  CAS  Google Scholar 

  103. Mayorov VI, Lowrey AJ, Biousse V, Newman NJ, Cline SD, Brown MD (2008) Mitochondrial oxidative phosphorylation in autosomal dominant optic atrophy. BMC Biochem 9:22

    Article  PubMed  CAS  Google Scholar 

  104. Benard G, Bellance N, James D et al (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120:838–848

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  106. Yu T, Robotham JL, Yoon Y (2006) Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA 103:2653–2658

    Article  PubMed  CAS  Google Scholar 

  107. Cao H, Garcia F, McNiven MA (1998) Differential distribution of dynamin isoforms in mammalian cells. Mol Biol Cell 9:2595–2609

    PubMed  CAS  Google Scholar 

  108. Ferguson SM, De Camilli P (2012) Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol 13:75–88

    PubMed  CAS  Google Scholar 

  109. Nakata T, Iwamoto A, Noda Y, Takemura R, Yoshikura H, Hirokawa N (1991) Predominant and developmentally regulated expression of dynamin in neurons. Neuron 7:461–469

    Article  PubMed  CAS  Google Scholar 

  110. Ferguson SM, Raimondi A, Paradise S et al (2009) Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev Cell 17:811–822

    Article  PubMed  CAS  Google Scholar 

  111. Nakata T, Takemura R, Hirokawa N (1993) A novel member of the dynamin family of GTP-binding proteins is expressed specifically in the testis. J Cell Sci 105:1–5

    PubMed  CAS  Google Scholar 

  112. Cook T, Mesa K, Urrutia R (1996) Three dynamin-encoding genes are differentially expressed in developing rat brain. J Neurochem 67:927–931

    Article  PubMed  CAS  Google Scholar 

  113. Gray NW, Fourgeaud L, Huang B (2003) Dynamin 3 is a component of the postsynapse, where it interacts with mGluR5 and Homer. Curr Biol 13:510–515

    Article  PubMed  CAS  Google Scholar 

  114. Ferguson SM, Brasnjo G, Hayashi M et al (2007) A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science 316:570–574

    Article  PubMed  CAS  Google Scholar 

  115. Ono T, Isobe K, Nakada K, Hayashi JI (2001) Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet 28:272–275

    Article  PubMed  CAS  Google Scholar 

  116. Nakada K, Inoue K, Ono T et al (2001) Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 7:934–940

    Article  PubMed  CAS  Google Scholar 

  117. Khan SM, Smigrodzki RM, Swerdlow RH (2007) Cell and animal models of mtDNA biology: progress and prospects. Am J Physiol Cell Physiol 292:C658–C669

    Article  PubMed  CAS  Google Scholar 

  118. Sharov VG, Goussev A, Lesch M, Goldstein S, Sabbah HN (1998) Abnormal mitochondrial function in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol 30:1757–1762

    Article  PubMed  CAS  Google Scholar 

  119. Zak R, Rabinowitz M, Rajamanickam C, Merten S, Kwiatkowska-Patzer B (1980) Mitochondrial proliferation in cardiac hypertrophy. Basic Res Cardiol 75:171–178

    Article  PubMed  CAS  Google Scholar 

  120. Schaper J, Froede R, Hein S et al (1991) Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83:504–514

    Article  PubMed  CAS  Google Scholar 

  121. Kalra DK, Zoghbi WA (2002) Myocardial hibernation in coronary artery disease. Curr Atheroscler Rep 4:149–155

    Article  PubMed  Google Scholar 

  122. Duvezin-Caubet S, Jagasia R, Wagener J et al (2006) Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281:37972–37979

    Article  PubMed  CAS  Google Scholar 

  123. Makino A, Suarez J, Gawlowski T et al (2011) Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol 300:R1296–R1302

    Article  PubMed  CAS  Google Scholar 

  124. Papanicolaou KN, Khairallah RJ, Ngoh GA et al (2011) Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 31:1309–1328

    Article  PubMed  CAS  Google Scholar 

  125. Chen Y, Liu Y, Dorn GW II et al (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109:1327–1331

    Article  PubMed  CAS  Google Scholar 

  126. Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562

    Article  PubMed  CAS  Google Scholar 

  127. Chen H, Vermulst M, Wang YE et al (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280–289

    Article  PubMed  CAS  Google Scholar 

  128. Dec GW, Fuster V (1994) Idiopathic dilated cardiomyopathy. N Engl J Med 331:1564–1575

    Article  PubMed  CAS  Google Scholar 

  129. Seidman JG, Seidman C (2001) The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell 104:557–567

    Article  PubMed  CAS  Google Scholar 

  130. Karkkainen S, Peuhkurinen K (2007) Genetics of dilated cardiomyopathy. Ann Med 39:91–107

    Article  PubMed  CAS  Google Scholar 

  131. Baandrup U, Florio RA, Roters F, Olsen EG (1981) Electron microscopic investigation of endomyocardial biopsy samples in hypertrophy and cardiomyopathy. A semiquantitative study in 48 patients. Circulation 63:1289–1298

    Article  PubMed  CAS  Google Scholar 

  132. Sun CN, Dhalla NS, Olson RE (1969) Formation of gigantic mitochondria in hypoxic isolated perfused rat hearts. Experientia 25:763–764

    Article  PubMed  CAS  Google Scholar 

  133. Ashrafian H, Docherty L, Leo V et al (2010) A mutation in the mitochondrial fission gene Dnm1 l leads to cardiomyopathy. PLoS Genet 6:e1001000

    Article  PubMed  CAS  Google Scholar 

  134. Ramachandran R, Surka M, Chappie JS et al (2007) The dynamin middle domain is critical for tetramerization and higher-order self-assembly. EMBO J 26:559–566

    Article  PubMed  CAS  Google Scholar 

  135. Mears JA, Ray P, Hinshaw JE (2007) A corkscrew model for dynamin constriction. Structure 15:1190–1202

    Article  PubMed  CAS  Google Scholar 

  136. Palaniyandi SS, Qi X, Yogalingam G, Ferreira JC, Mochly-Rosen D (2010) Regulation of mitochondrial processes: a target for heart failure. Drug Discov Today Dis Mech 7:e95–e102

    Article  PubMed  CAS  Google Scholar 

  137. Chen L, Gong Q, Stice JP, Knowlton AA (2009) Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 84:91–99

    Article  PubMed  CAS  Google Scholar 

  138. Molina AJ, Wikstrom JD, Stiles L et al (2009) Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes 58:2303–2315

    Article  PubMed  CAS  Google Scholar 

  139. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011

    Article  PubMed  CAS  Google Scholar 

  140. Arnoult D (2007) Mitochondrial fragmentation in apoptosis. Trends Cell Biol 17:6–12

    Article  PubMed  CAS  Google Scholar 

  141. Martinou JC, Youle RJ (2011) Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 21:92–101

    Article  PubMed  CAS  Google Scholar 

  142. Parra V, Eisner V, Chiong M et al (2008) Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res 77:387–397

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  145. Guo X, Chen KH, Guo Y, Liao H, Tang J, Xiao RP (2007) Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway. Circ Res 101:1113–1122

    Article  PubMed  CAS  Google Scholar 

  146. Shen T, Zheng M, Cao C et al (2007) Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis. J Biol Chem 282:23354–23361

    Article  PubMed  CAS  Google Scholar 

  147. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  PubMed  CAS  Google Scholar 

  148. Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H (2005) Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 280:25060–25070

    Article  PubMed  CAS  Google Scholar 

  149. Santel A, Frank S, Gaume B, Herrler M, Youle RJ, Fuller MT (2003) Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci 116:2763–2774

    Article  PubMed  CAS  Google Scholar 

  150. Lukyanenko V, Chikando A, Lederer WJ (2009) Mitochondria in cardiomyocyte Ca2+ signaling. Int J Biochem Cell Biol 41:1957–1971

    Article  PubMed  CAS  Google Scholar 

  151. Papanicolaou KN, Khairallah RJ, Ngoh GA et al (2011) Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 31:1309–1328

    Article  PubMed  CAS  Google Scholar 

  152. Tandler B, Hoppel CL (1972) Possible division of cardiac mitochondria. Anat Rec 173:309–323

    Article  PubMed  CAS  Google Scholar 

  153. Hom J, Yu T, Yoon Y, Porter G, Sheu SS (2010) Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes. Biochim Biophys Acta 1797:913–921

    Article  PubMed  CAS  Google Scholar 

  154. Hamacher-Brady A, Brady NR, Gottlieb RA, Gustafsson AB (2006) Autophagy as a protective response to Bnip3-mediated apoptotic signaling in the heart. Autophagy 2:307–309

    PubMed  CAS  Google Scholar 

  155. Matsui Y, Takagi H, Qu X et al (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922

    Article  PubMed  CAS  Google Scholar 

  156. Gottlieb RA, Gustafsson AB (2011) Mitochondrial turnover in the heart. Biochim Biophys Acta 1813:1295–1301

    Article  PubMed  CAS  Google Scholar 

  157. Kuzmicic J, Del Campo A, Lopez-Crisosto C et al (2011) Mitochondrial dynamics: a potential new therapeutic target for heart failure. Rev Esp Cardiol 64:916–923

    Article  PubMed  Google Scholar 

  158. Ng AC (2010) Integrative systems biology and networks in autophagy. Semin Immunopathol 32:355–361

    Article  PubMed  Google Scholar 

  159. Ziviani E, Whitworth AJ (2010) How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 6:660–662

    Article  PubMed  Google Scholar 

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Correspondence to José Marín-García.

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Marín-García, J., Akhmedov, A.T. & Moe, G.W. Mitochondria in heart failure: the emerging role of mitochondrial dynamics. Heart Fail Rev 18, 439–456 (2013). https://doi.org/10.1007/s10741-012-9330-2

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