[Frontiers in Bioscience, Landmark, 20, 229-246, January 1, 2015]

Morphological control of mitochondrial bioenergetics

Tianzheng Yu 1 , Li Wang 1 , Yisang Yoon 1

1Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Molecular mechanisms of mitochondrial fission and fusion
    3.1. Mitochondrial fission
      3.1.1. Mitochondrial fission by DLP1 and its receptors
      3.1.2. Regulation of mitochondrial fission through DLP1 phosphorylation
    3.2. Mitochondrial fusion
      3.2.1. Mitochondrial fusion by Mfn and OPA1
      3.2.2. More on Mfn and OPA1
4. Mitochondrial bioenergetics and morphology
    4.1. Mitochondrial bioenergetics – a simplistic view
    4.2. Mitochondrial morphology and energetic states: bi-directional influence
    4.3. Mitochondrial morphology and functionality in physio-pathological settings
    4.4. Control of respiration coupling: a mechanism linking mitochondrial morphology and bioenergetic activity?
5. Conclusion
6. Acknowlegements
7. References

1. ABSTRACT

The major function of mitochondria is production and supply of cellular energy. Mitochondria are highly dynamic organelles undergoing frequent shape changes via fission and fusion. Many studies have elucidated the molecular components mediating fission and fusion and their regulatory mechanisms, and mitochondrial shape change is now recognized as an essential cellular process that is closely associated with functional states of mitochondria. This review updates the recent advancements in fission and fusion mechanisms, and discusses the bi-directional relationship between mitochondrial morphology and energetic states in physio-pathological settings.

7. REFERENCES

1. Bereiter-Hahn J & Voth M (1994) Dynamics of mitochondria in living cells: shape changes, dislocation, fusion, and fission of mitochondria. Microsc. Res. Tech. 27:198-219.
DOI: 10.1002/jemt.1070270303

2. Yoon Y (2005) Regulation of mitochondrial dynamics: Another process modulated by Ca2+ signal? Sci. STKE 2005:pe18.
DOI: 10.1126/stke.2802005pe18

3. Yoon Y, Galloway CA, Jhun BS, & Yu T (2011) Mitochondrial dynamics in diabetes. Antioxid Redox Signal 14(3):439-457.
DOI: 10.1089/ars.2010.3286

4. McBride HM, Neuspiel M, & Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16(14):R551-560.
DOI: 10.1016/j.cub.2006.06.054

5. Praefcke GJ & McMahon HT (2004) The dynamin superfamily: universal membrane tubulation and fission molecules? Nat. Rev. Mol. Cell Biol. 5:133-147.
DOI: 10.1038/nrm1313

6. McNiven MA, Cao H, Pitts KR, & Yoon Y (2000) The dynamin family of mechanoenzymes: pinching in new places. Trends Biochem. Sci. 25(3):115-120.
DOI: 10.1016/S0968-0004(99)01538-8

7. Takei K, McPherson PS, Schmid SL, & De Camilli P (1995) Tubular membrane invaginations coated by dynamin rings are induced by GTP-gS in nerve terminals. Nature 374:186-190.
DOI: 10.1038/374186a0

8. Sweitzer SM & Hinshaw JE (1998) Dynamin undergoes a GTP-dependent conformational change causing vesiculation. Cell 93(6):1021-1029.
DOI: 10.1016/S0092-8674(00)81207-6

9. Yoon Y, Pitts KR, & McNiven MA (2001) Mammalian dynamin-like protein DLP1 tubulates membranes. Mol. Biol. Cell 12(9):2894-2905.
DOI: 10.1091/mbc.12.9.2894

10. Smirnova E, Griparic L, Shurland DL, & van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12(8):2245-2256.
DOI: 10.1091/mbc.12.8.2245

11. Ingerman E, et al. (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. J Cell Biol 170(7):1021-1027.
DOI: 10.1083/jcb.200506078

12. Mears JA, et al. (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat Struct Mol Biol 18(1):20-26.
DOI: 10.1038/nsmb.1949

13. Yoon Y, Krueger EW, Oswald BJ, & McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol. Cell. Biol. 23(15):5409-5420.
DOI: 10.1128/MCB.23.15.5409-5420.2003

14. Yu T, Fox RJ, Burwell LS, & Yoon Y (2005) Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1. J. Cell Sci. 118:4141-4151.
DOI: 10.1242/jcs.02537

15. Stojanovski D, Koutsopoulos OS, Okamoto K, & Ryan MT (2004) Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J. Cell Sci. 117(Pt 7):1201-1210.
DOI: 10.1242/jcs.01058

16. James DI, Parone PA, Mattenberger Y, & Martinou JC (2003) hFis1, a novel component of the mammalian mitochondrial fission machinery. J. Biol. Chem. 278:36373-36379.
DOI: 10.1074/jbc.M303758200

17. Suzuki M, Jeong SY, Karbowski M, Youle RJ, & Tjandra N (2003) The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. J. Mol. Biol. 334(3):445-458.
DOI: 10.1016/j.jmb.2003.09.064

18. 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(11):5001-5011.
DOI: 10.1091/mbc.E04-04-0294

19. 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(6):2402-2412.
DOI: 10.1091/mbc.E07-12-1287

20. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K. (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191(6):1141-1158.
DOI: 10.1083/jcb.201007152

21. Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT. (2011) MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep 12(6):565-573.
DOI: 10.1038/embor.2011.54

22. Zhao J, Liu T, Jin S, Wang X, Qu M, Uhlén P, Tomilin N, Shupliakov O, Lendahl U, Nistér M. (2011) Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. EMBO J 30(14):2762-2778.
DOI: 10.1038/emboj.2011.198

23. Palmer CS1, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT. (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem 288(38):27584-27593.
DOI: 10.1074/jbc.M113.479873

24. Loson OC, Song Z, Chen H, & Chan DC (2013) Fis1, Mff, MiD49 and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell.
DOI: 10.1091/mbc.E12-10-0721

25. Friedman JR, et al. (2011) ER tubules mark sites of mitochondrial division. Science 334(6054):358-362.
DOI: 10.1126/science.1207385

26. Kornmann B, et al. (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325(5939):477-481.
DOI: 10.1126/science.1175088

27. Murley A, et al. (2013) ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. eLife 2:e00422.
DOI: 10.7554/eLife.00422

28. Korobova F, Ramabhadran V, & Higgs HN (2013) An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339(6118):464-467.
DOI: 10.1126/science.1228360

29. Stavru F, Palmer AE, Wang C, Youle RJ, & Cossart P (2013) Atypical mitochondrial fission upon bacterial infection. Proc Natl Acad Sci U S A.
DOI: 10.1073/pnas.1315784110

30. Stavru F, Bouillaud F, Sartori A, Ricquier D, & Cossart P (2011) Listeria monocytogenes transiently alters mitochondrial dynamics during infection. Proc Natl Acad Sci U S A 108(9):3612-3617.
DOI: 10.1073/pnas.1100126108

31. Raturi A & Simmen T (2013) Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta 1833(1):213-224.
DOI: 10.1016/j.bbamcr.2012.04.013

32. Szabadkai G, et al. (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175(6):901-911.
DOI: 10.1083/jcb.200608073

33. de Brito OM & Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456(7222):605-610.
DOI: 10.1038/nature07534

34. Boehning D, et al. (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat. Cell Biol. 5(12):1051-1061.
DOI: 10.1038/ncb1063

35. Li J, et al. (2010) miR-30 regulates mitochondrial fission through targeting p53 and the dynamin-related protein-1 pathway. PLoS Genet 6(1):e1000795.
DOI: 10.1371/journal.pgen.1000795

36. Wang JX, et al. (2011) miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med 17(1):71-78.
DOI: 10.1038/nm.2282

37. Wang K, et al. (2012) miR-484 regulates mitochondrial network through targeting Fis1. Nature communications 3:781.
DOI: 10.1038/ncomms1770

38. Cho DH, et al. (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324(5923):102-105.
DOI: 10.1126/science.1171091

39. Gawlowski T, et al. (2012) Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-beta-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem 287(35):30024-30034.
DOI: 10.1074/jbc.M112.390682

40. Guo C, et al. (2013) SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. Embo J 32(11):1514-1528.
DOI: 10.1038/emboj.2013.65

41. Horn SR, et al. (2011) Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability. Mol Biol Cell 22(8):1207-1216.
DOI: 10.1091/mbc.E10-07-0567

42. Nakamura N, Kimura Y, Tokuda M, Honda S, & Hirose S (2006) MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep 7(10):1019-1022.
DOI: 10.1038/sj.embor.7400790

43. Yonashiro R, et al. (2006) A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics. Embo J 25(15):3618-3626.
DOI: 10.1038/sj.emboj.7601249

44. 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(3):439-450.
DOI: 10.1083/jcb.200610042

45. Taguchi N, Ishihara N, Jofuku A, Oka T, & Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282(15):11521-11529.
DOI: 10.1074/jbc.M607279200

46. Qi X, Disatnik MH, Shen N, Sobel RA, & Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell 22(2):256-265.
DOI: 10.1091/mbc.E10-06-0551

47. Yu T, Jhun BS, & Yoon Y (2011) High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Antioxid Redox Signal 14(3):425-437.
DOI: 10.1089/ars.2010.3284

48. Kashatus DF, et al. (2011) RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol 13(9):1108-1115.
DOI: 10.1038/ncb2310

49. Chang CR & Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282(30):21583-21587.
DOI: 10.1074/jbc.C700083200

50. Cribbs JT & Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8(10):939-944.
DOI: 10.1038/sj.embor.7401062

51. Han XJ, et al. (2008) CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182(3):573-585.
DOI: 10.1083/jcb.200802164

52. Wang W, et al. (2012) Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 15(2):186-200.
DOI: 10.1016/j.cmet.2012.01.009

53. Gomes LC, Di Benedetto G, & Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589-598.
DOI: 10.1038/ncb2220

54. Kim H, et al. (2011) Fine-Tuning of Drp1/Fis1 Availability by AKAP121/Siah2 Regulates Mitochondrial Adaptation to Hypoxia. Mol Cell 44(4):532-544.
DOI: 10.1016/j.molcel.2011.08.045

55. Cereghetti GM, et al. (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A 105(41):15803-15808.
DOI: 10.1073/pnas.0808249105

56. Merrill RA, Slupe AM, & Strack S (2012) N-terminal phosphorylation of protein phosphatase 2A/Bbeta2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival. FEBS J. 280(2):662-73.
DOI: 10.1111/j.1742-4658.2012.08631.x

57. Dickey AS & Strack S (2011) PKA/AKAP1 and PP2A/Bbeta2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics. J Neurosci 31(44):15716-15726.
DOI: 10.1523/JNEUROSCI.3159-11.2011

58. Wang Z, Jiang H, Chen S, Du F, & Wang X (2012) The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148(1-2):228-243.
DOI: 10.1016/j.cell.2011.11.030

59. Santel A, et al. (2003) Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J. Cell Sci. 116(Pt 13):2763-2774.
DOI: 10.1242/jcs.00479

60. Eura Y, Ishihara N, Yokota S, & Mihara K (2003) Two mitofusin proteins, mammalian homologues of FZO, with distinct functions are both required for mitochondrial fusion. J. Biochem. 134:333-344.
DOI: 10.1093/jb/mvg150

61. 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. 115(Pt 8):1663-1674.

62. Koshiba T, et al. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858-862.
DOI: 10.1126/science.1099793

63. Chen H, et al. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 160:189-200.
DOI: 10.1083/jcb.200211046

64. Ishihara N, Eura Y, & Mihara K (2004) Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J. Cell Sci. 117:6535-6546.
DOI: 10.1242/jcs.01565

65. Hoppins S, et al. (2011) The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes. Mol Cell 41(2):150-160.
DOI: 10.1016/j.molcel.2010.11.030

66. Delettre C, et al. (2001) Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet 109(6):584-591.
DOI: 10.1007/s00439-001-0633-y

67. Ishihara N, Fujita Y, Oka T, & Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. Embo J 25(13):2966-2977.
DOI: 10.1038/sj.emboj.7601184

68. Song Z, Chen H, Fiket M, Alexander C, & Chan DC (2007) OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 178(5):749-755.
DOI: 10.1083/jcb.200704110

69. Ban T, Heymann JA, Song Z, Hinshaw JE, & Chan DC (2010) OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet 19(11):2113-2122.
DOI: 10.1093/hmg/ddq088

70. 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(15):3525-3532.
DOI: 10.1091/mbc.E09-03-0252

71. Sesaki H & Jensen RE (2004) Ugo1p links the Fzo1p and Mgm1p GTPases for mitochondrial fusion. J. Biol. Chem. 279:28298-28303.
DOI: 10.1074/jbc.M401363200

72. Olichon A, et al. (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278(10):7743-7746.
DOI: 10.1074/jbc.C200677200

73. Arnoult D, Grodet A, Lee YJ, Estaquier J, & Blackstone C (2005) Release of OPA1 during apoptosis participates in the rapid and complete release of cytochrome c and subsequent mitochondrial fragmentation. J Biol Chem 280(42):35742-35750.
DOI: 10.1074/jbc.M505970200

74. Frezza C, et al. (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126:177-189.
DOI: 10.1016/j.cell.2006.06.025

75. Cogliati S, et al. (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155(1):160-171.
DOI: 10.1016/j.cell.2013.08.032

76. Ishihara N, Jofuku A, Eura Y, & Mihara K (2003) Regulation of mitochondrial morphology by membrane potential, and DRP1-dependent division and FZO1-dependent fusion reaction in mammalian cells. Biochem. Biophys. Res. Commun. 301(4):891-898.
DOI: 10.1016/S0006-291X(03)00050-0

77. Legros F, Lombes A, Frachon P, & Rojo M (2002) Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol. Biol. Cell 13(12):4343-4354.
DOI: 10.1091/mbc.E02-06-0330

78. Duvezin-Caubet S, et al. (2006) Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281(49):37972-37979.
DOI: 10.1074/jbc.M606059200

79. Cipolat S, et al. (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126:163-175.
DOI: 10.1016/j.cell.2006.06.021

80. Duvezin-Caubet S, et al. (2007) OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria. Mol Biol Cell 18(9):3582-3590.
DOI: 10.1091/mbc.E07-02-0164

81. Ehses S, et al. (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 187(7):1023-1036.
DOI: 10.1083/jcb.200906084

82. Griparic L, Kanazawa T, & van der Bliek AM (2007) Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 178(5):757-764.
DOI: 10.1083/jcb.200704112

83. Head B, Griparic L, Amiri M, Gandre-Babbe S, & van der Bliek AM (2009) Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol 187(7):959-966.
DOI: 10.1083/jcb.200906083

84. Twig G, et al. (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo J 27(2):433-446.
DOI: 10.1038/sj.emboj.7601963

85. Karbowski M, Neutzner A, & Youle RJ (2007) The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178(1):71-84.
DOI: 10.1083/jcb.200611064

86. Park YY, et al. (2010) Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1. J Cell Sci 123(Pt 4):619-626.
DOI: 10.1242/jcs.061481

87. Sugiura A, et al. (2013) MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol Cell 51(1):20-34.
DOI: 10.1016/j.molcel.2013.04.023

88. Tanaka A, et al. (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191(7):1367-1380.
DOI: 10.1083/jcb.201007013

89. Gegg ME, et al. (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19(24):4861-4870.
DOI: 10.1093/hmg/ddq419

90. Chen Y & Dorn GW, 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340(6131):471-475.
DOI: 10.1126/science.1231031

91. Leboucher GP, et al. (2012) Stress-Induced Phosphorylation and Proteasomal Degradation of Mitofusin 2 Facilitates Mitochondrial Fragmentation and Apoptosis. Mol Cell 47(4):547-557.
DOI: 10.1016/j.molcel.2012.05.041

92. Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144-148.
DOI: 10.1038/191144a0

93. Nicholls DG & Ferguson SJ (1992) Bioenergetics 2 (Academic Pr, San Diego, CA).

94. Bouillaud F, Ricquier D, Thibault J, & Weissenbach J (1985) Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein. Proc Natl Acad Sci U S A 82(2):445-448.
DOI: 10.1073/pnas.82.2.445

95. Jezek P & Garlid KD (1998) Mammalian mitochondrial uncoupling proteins. Int J Biochem Cell Biol 30(11):1163-1168.
DOI: 10.1016/S1357-2725(98)00076-4

96. Inoue M, et al. (2003) Mitochondrial generation of reactive oxygen species and its role in aerobic life. Current medicinal chemistry 10(23):2495-2505.
DOI: 10.2174/0929867033456477

97. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(Pt 2):335-344.
DOI: 10.1113/jphysiol.2003.049478

98. Turrens JF (1997) Superoxide production by the mitochondrial respiratory chain. Biosci Rep 17(1):3-8.
DOI: 10.1023/A:1027374931887

99. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annual review of biochemistry 64:97-112.
DOI: 10.1146/annurev.bi.64.070195.000525

100. Korshunov SS, Skulachev VP, & Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416:15-18.
DOI: 10.1016/S0014-5793(97)01159-9

101. Du XL, et al. (2001) Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. 108:1341-1348.
DOI: 10.1172/JCI11235

102. Nishikawa T, et al. (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790.
DOI: 10.1038/35008121

103. Echtay KS, Murphy MP, Smith RA, Talbot DA, & Brand MD (2002) Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem 277(49):47129-47135.
DOI: 10.1074/jbc.M208262200

104. Echtay KS, et al. (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415(6867):96-99.
DOI: 10.1038/415096a

105. Benard G, et al. (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120(Pt 5):838-848.
DOI: 10.1242/jcs.03381

106. De Vos KJ, Allan VJ, Grierson AJ, & Sheetz MP (2005) Mitochondrial function and actin regulate dynamin-related protein 1-dependent mitochondrial fission. Curr. Biol. 15:678-683.
DOI: 10.1016/j.cub.2005.02.064

107. Liot G, et al. (2009) Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Cell Death Differ 16(6):899-909.
DOI: 10.1038/cdd.2009.22

108. Barsoum MJ, et al. (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. Embo J 25(16):3900-3911.
DOI: 10.1038/sj.emboj.7601253

109. Meeusen S, et al. (2006) Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127(2):383-395.
DOI: 10.1016/j.cell.2006.09.021

110. Chen H, Chomyn A, & Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280:26185-26192.
DOI: 10.1074/jbc.M503062200

111. Parone PA, et al. (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3(9):e3257.
DOI: 10.1371/journal.pone.0003257

112. Ishihara N, et al. (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11(8):958-966.
DOI: 10.1038/ncb1907

113. Ong SB, et al. (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121(18):2012-2022.
DOI: 10.1161/CIRCULATIONAHA.109.906610

114. Shenouda SM, et al. (2011) Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation 124(4):444-453.
DOI: 10.1161/CIRCULATIONAHA.110.014506

115. Yu T, Sheu SS, Robotham JL, & Yoon Y (2008) Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 79(2):341-351.
DOI: 10.1093/cvr/cvn104

116. 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. U S A 103:2653-2658.
DOI: 10.1073/pnas.0511154103

117. Molina AJ, et al. (2009) Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes 58(10):2303-2315.
DOI: 10.2337/db07-1781

118. Galloway CA, et al. (2012) Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress. Diabetes 61(8):2093-2104.
DOI: 10.2337/db11-1640

119. Carneiro L, et al. (2012) Importance of mitochondrial dynamin-related protein 1 in hypothalamic glucose sensitivity in rats. Antioxid Redox Signal 17(3):433-444.
DOI: 10.1089/ars.2011.4254

120. Tondera D, et al. (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. Embo J 28(11):1589-1600.
DOI: 10.1038/emboj.2009.89

121. Rambold AS, Kostelecky B, Elia N, & Lippincott-Schwartz J (Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A 108(25):10190-10195.
DOI: 10.1073/pnas.1107402108

122. Morton GJ, Cummings DE, Baskin DG, Barsh GS, & Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443(7109):289-295.
DOI: 10.1038/nature05026

123. Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, & Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661-671.

124. Schneeberger M, Dietrich MO, Sebastián D, Imbernón M, Casta-o C, Garcia A, Esteban Y, Gonzalez-Franquesa A, Rodríguez IC, Bortolozzi A, Garcia-Roves PM, Gomis R, Nogueiras R, Horvath TL, Zorzano A, Claret M. (2013) Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155(1):172-187.
DOI: 10.1016/j.cell.2013.09.003

125. Dietrich MO, Liu ZW, & Horvath TL (2013) Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155(1):188-199.
DOI: 10.1016/j.cell.2013.09.004

126. Jhun BS, Lee H, Jin ZG, & Yoon Y (2013) Glucose stimulation induces dynamic change of mitochondrial morphology to promote insulin secretion in the insulinoma cell line INS-1E. PLoS ONE 8(4):e60810.
DOI: 10.1371/journal.pone.0060810

127. Ichas F, Jouaville LS, & Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89(7):1145-1153.
DOI: 10.1016/S0092-8674(00)80301-3

128. Huser J & Blatter LA (1999) Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore. Biochem J 343 Pt 2:311-317.
DOI: 10.1042/0264-6021:3430311

129. Hackenbrock CR (1966) Ultrastructural bases for metabolically linked mechanical activity in mitochondria: I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. J. Cell Biol. 30:269-297.
DOI: 10.1083/jcb.30.2.269

130. Mitra K, Wunder C, Roysam B, Lin G, & Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A 106(29):11960-11965.
DOI: 10.1073/pnas.0904875106

Key Words: Mitochondria, Fission, Fusion, Morphology, Dynamics, DLP1, Drp1, Mfn, OPA1, Bioenergetics, Review

Send correspondence to: Yisang Yoon, Department of Physiology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, Tel: 706-721-7859, Fax: 706-721- 7299, E-mail: yyoon@gru.edu