Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction

Frontiers in Aging Neuroscience

Volumn 7, Issue JUN, 2015, Pages

  Zorzano, Antonio ^a,b,c   Claret, Marc ^c,d  

^a INSTITUTE FOR RESEARCH IN BIOMEDICINE   (Spain)

^b UNIVERSITY OF BARCELONA   (Spain)

^c INSTITUTO DE SALUD CARLOS III   (Spain)

^d INSTITUT D INVESTIGACIONS BIOMÈDIQUES AUGUST PI I SUNYER IDIBAPS   (Spain)

Author keywords

Food intake; Mitochondrial fission; Mitochondrial fusion; Mitofusin 2; Neurodegenerative diseases; Obesity

Indexed keywords

AGOUTI RELATED PROTEIN; DYNAMIN RELATEDPROTEIN1; GANGLIOSIDE INDUCED DIFFERENTIATION ASSOCIATED PROTEIN 1; GHRELIN; LEPTIN; MELANOCORTIN RECEPTOR; MEMBRANE PROTEIN; MFF PROTEIN; MID49 PROTEIN; MID51 PROTEIN; MITOCHONDRIAL FUSION PROTEIN; MITOCHONDRIAL PROTEIN; MITOFUSIN 1; MITOFUSIN 2; NEUROPEPTIDE Y; OPA1 PROTEIN; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE; UNCLASSIFIED DRUG;

ARCUATE NUCLEUS; AUTOSOMAL DOMINANT OPTIC ATROPHY; CELLULAR PARAMETERS; DISEASE ASSOCIATION; ENDOPLASMIC RETICULUM; ENERGY BALANCE; FOOD INTAKE; GENE MUTATION; HEREDITARY MOTOR SENSORY NEUROPATHY; HUMAN; HUNTINGTON CHOREA; HYPOTHALAMUS DISEASE; MFN2 GENE; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL FISSION; MITOCHONDRIAL FUSION; NERVE DEGENERATION; OPA1 GENE; PARKINSON DISEASE; PATHOPHYSIOLOGY; PROTEIN FUNCTION; REVIEW;

EID: 84936139805     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2015.00101     Document Type: Review

References (230)

1. Akepati, V. R., Muller, E. C., Otto, A., Strauss, H. M., Portwich, M., and Alexander, C. (2008). Characterization of OPA1 isoforms isolated from mouse tissues. J. Neurochem. 106, 372-383. doi: 10.1111/j.1471-4159.2008.05401.x
2. Alavi, M. V., Bette, S., Schimpf, S., Schuettauf, F., Schraermeyer, U., Wehrl, H. F., et al. (2007). A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain 130, 1029-1042. doi: 10.1093/brain/awm005
3. Al-Qassab, H., Smith, M. A., Irvine, E. E., Guillermet-Guibert, J., Claret, M., Choudhury, A. I., et al. (2009). Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab. 10, 343-354. doi: 10.1016/j.cmet.2009.09.008
4. Amati-Bonneau, P., Valentino, M. L., Reynier, P., Gallardo, M. E., Bornstein, B., Boissière, A., et al. (2008). OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes. Brain 131, 338-351. doi: 10.1093/brain/awm298
5. Amiott, E. A., Lott, P., Soto, J., Kang, P. B., McCaffery, J. M., DiMauro, S., et al. (2008). Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations. Exp. Neurol. 211, 115-127. doi: 10.1016/j.expneurol.2008.01.010
6. Ammar, N., Nelis, E., Merlini, L., Barisic, N., Amouri, R., Ceuterick, C., et al. (2003). Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease. Neuromuscul. Disord. 13, 720-728. doi: 10.1016/S0960-8966(03)00093-2
7. Andrews, Z. B., Liu, Z. W., Walllingford, N., Erion, D. M., Borok, E., Friedman, J. M., et al. (2008). UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846-851. doi: 10.1038/nature07181
8. Area-Gomez, E., Del Carmen Lara Castillo, M., Tambini, M. D., Guardia-Laguarta, C., de Groof, A. J., Madra, M., et al. (2012). Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31, 4106-4123. doi: 10.1038/emboj.2012.202
9. Atasoy, D., Betley, J. N., Su, H. H., and Sternson, S. M. (2012). Deconstruction of a neural circuit for hunger. Nature 488, 172-177. doi: 10.1038/nature11270
10. Bach, D., Pich, S., Soriano, F. X., Vega, N., Baumgartner, B., Oriola, J., 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. doi: 10.1074/jbc.M212754200
11. Baloh, R. H., Schmidt, R. E., Pestronk, A., and Milbrandt, J. (2007). Altered axonal mitochondrial transport in the pathogenesis of charcot-marie-tooth disease from mitofusin 2 mutations. J. Neurosci. 27, 422-430. doi: 10.1523/JNEUROSCI.4798-06.2007
12. Baricault, L., Segui, B., Guegand, L., Olichon, A., Valette, A., Larminat, F., et al. (2007). OPA1 cleavage depends on decreased mitochondrial ATP level and bivalent metals. Exp. Cell Res. 313, 3800-3808. doi: 10.1016/j.yexcr.2007.08.008
13. Baris, O., Delettre, C., Amati-Bonneau, P., Surget, M.-O., Charlin, J.-F., Catier, A., et al. (2003). Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy. Hum. Mutat. 21, 656. doi: 10.1002/humu.9152
14. Barsoum, M. J., Yuan, H., Gerencser, A. A., Liot, G., Kushnareva, Y., Graber, S., et al. (2006). Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J. 25, 3900-3911. doi: 10.1038/sj.emboj.7601253
15. Baxter, R. V., Ben Othmane, K., Rochelle, J. M., Stajich, J. E., Hulette, C., Dew-Knight, S., et al. (2002). Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat. Genet. 30, 21-22. doi: 10.1038/ng796
16. Bereiter-Hahn, J., and Voth, M. (1994). Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc. Res. Tech. 27, 198-219. doi: 10.1002/jemt.1070270303
17. Berger, P., Young, P., and Suter, U. (2002). Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics 4, 1-15. doi: 10.1007/s10048-002-0130-z
18. Berridge, M. J. (2002). The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32, 235-249. doi: 10.1016/S0143416002001823
19. Bleazard, W., McCaffery, J. M., King, E. J., Bale, S., Mozdy, A., Tieu, Q., et al. (1999). The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat. Cell Biol. 1, 298-304. doi: 10.1038/13014
20. Boerkoel, C. F., Takashima, H., Nakagawa, M., Izumo, S., Armstrong, D., Butler, I., et al. (2003). CMT4A: identification of a hispanic GDAP1 founder mutation. Ann. Neurol. 53, 400-405. doi: 10.1002/ana.10505
21. Brouillet, E., Hantraye, P., Ferrante, R. J., Dolan, R., Leroy-Willig, A., Kowall, N. W., et al. (1995). Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc. Natl. Acad. Sci. U.S.A. 92, 7105-7109. doi: 10.1073/pnas.92.15.7105
22. Cardenas, C., Miller, R. A., Smith, I., Bui, T., Molgo, J., Muller, M., et al. (2010). Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142, 270-283. doi: 10.1016/j.cell.2010.06.007
23. Cassereau, J., Chevrollier, A., Gueguen, N., Desquiret, V., Verny, C., Nicolas, G., et al. (2011). Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. Exp. Neurol. 227, 31-41. doi: 10.1016/j.expneurol.2010.09.006
24. Cereghetti, G. M., Stangherlin, A., Martins De Brito, O., Chang, C. R., Blackstone, C., Bernardi, P., et al. (2008). Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc. Natl. Acad. Sci. U.S.A. 105, 15803-15808. doi: 10.1073/pnas.0808249105
25. Chami, M., Oules, B., Szabadkai, G., Tacine, R., Rizzuto, R., and Paterlini-Brechot, P. (2008). Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol. Cell. 32, 641-651. doi: 10.1016/j.molcel.2008.11.014
26. Chan, N. C., Salazar, A. M., Pham, A. H., Sweredoski, M. J., Kolawa, N. J., Graham, R. L., et al. (2011). Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726-1737. doi: 10.1093/hmg/ddr048
27. Chang, C. R., and Blackstone, C. (2007). Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J. Biol. Chem. 282, 21583-21587. doi: 10.1074/jbc.C700083200
28. Chen, H., and Chan, D. C. (2005). Emerging functions of mammalian mitochondrial fusion and fission. Hum. Mol. Genet. 14, R283-R289. doi: 10.1093/hmg/ddi270
29. Chen, H., Chomyn, A., and Chan, D. C. (2005). Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280, 26185-26192. doi: 10.1074/jbc.M503062200
30. Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., and Chan, D. C. (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
31. Chen, H., McCaffery, J. M., and Chan, D. C. (2007). Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130, 548-562. doi: 10.1016/j.cell.2007.06.026
32. Chen, H. Y., Trumbauer, M. E., Chen, A. S., Weingarth, D. T., Adams, J. R., Frazier, E. G., et al. (2004b). Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 145, 2607-2612. doi: 10.1210/en.2003-1596
33. Chen, K. H., Dasgupta, A., Ding, J., Indig, F. E., Ghosh, P., and Longo, D. L. (2014). Role of mitofusin 2 (Mfn2) in controlling cellular proliferation. FASEB J. 28, 382-394. doi: 10.1096/fj.13-230037
34. Chen, K. H., Guo, X., Ma, D., Guo, Y., Li, Q., Yang, D., et al. (2004a). Dysregulation of HSG triggers vascular proliferative disorders. Nat. Cell Biol. 6, 872-883. doi: 10.1038/ncb1161
35. Cheung, C. C., Clifton, D. K., and Steiner, R. A. (1997). Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138, 4489-4492. doi: 10.1210/endo.138.10.5570
36. Cho, D.-H., Nakamura, T., Fang, J., Cieplak, P., Godzik, A., Gu, Z., et al. (2009). S-Nitrosylation of Drp1 mediates ß-amyloid-related mitochondrial fission and neuronal injury. Science 324, 102-105. doi: 10.1126/science.1171091
37. Chung, K. W., Kim, S. B., Park, K. D., Choi, K. G., Lee, J. H., Eun, H. W., et al. (2006). Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129, 2103-2118. doi: 10.1093/brain/awl174
38. Cipolat, S., De Brito, O. M., Dal Zilio, B., and Scorrano, L. (2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl. Acad. Sci. U.S.A. 101, 15927-15932. doi: 10.1073/pnas.0407043101
39. Claret, M., Smith, M. A., Batterham, R. L., Selman, C., Choudhury, A. I., Fryer, L. G., et al. (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J. Clin. Invest. 117, 2325-2336. doi: 10.1172/JCI31516
40. Cogliati, S., Frezza, C., Soriano, M. E., Varanita, T., Quintana-Cabrera, R., Corrado, M., et al. (2013). Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155, 160-171. doi: 10.1016/j.cell.2013.08.032
41. Coppola, A., Liu, Z. W., Andrews, Z. B., Paradis, E., Roy, M. C., Friedman, J. M., et al. (2007). A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab. 5, 21-33. doi: 10.1016/j.cmet.2006.12.002
42. Cortese, J. D., Voglino, L. A., and Hackenbrock, C. R. (1998). Novel fluorescence membrane fusion assays reveal GTP-dependent fusogenic properties of outer mitochondrial membrane-derived proteins. Biochim. Biophys. Acta 1371, 185-198. doi: 10.1016/S0005-2736(97)00266-6
43. Costa, V., Giacomello, M., Hudec, R., Lopreiato, R., Ermak, G., Lim, D., et al. (2010). Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli. EMBO Mol. Med. 2, 490-503. doi: 10.1002/emmm.201000102
44. Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdan, M. G., Diano, S., Horvath, T. L., et al. (2001). Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480-484. doi: 10.1038/35078085
45. Cowley, M. A., Smith, R. G., Diano, S., Tschop, M., Pronchuk, N., Grove, K. L., et al. (2003). The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649-661. doi: 10.1016/S0896-6273(03)00063-1
46. Cribbs, J. T., and Strack, S. (2007). Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 8, 939-944. doi: 10.1038/sj.embor.7401062
47. Cuesta, A., Pedrola, L., Sevilla, T., Garcia-Planells, J., Chumillas, M. J., Mayordomo, F., et al. (2002). The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat. Genet. 30, 22-25. doi: 10.1038/ng798
48. Cyr, N. E., Toorie, A. M., Steger, J. S., Sochat, M. M., Hyner, S., Perello, M., et al. (2013). Mechanisms by which the orexigen NPY regulates anorexigenic alpha-MSH and TRH. Am. J. Physiol. Endocrinol. Metab. 304, E640-E650. doi: 10.1152/ajpendo.00448.2012
49. Davies, V. J., Hollins, A. J., Piechota, M. J., Yip, W., Davies, J. R., White, K. E., 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. doi: 10.1093/hmg/ddm079
50. de Brito, O. M., and Scorrano, L. (2008). Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605-610. doi: 10.1038/nature07534
51. Delettre, C., Griffoin, J. M., Kaplan, J., Dollfus, H., Lorenz, B., Faivre, L., et al. (2001). Mutation spectrum and splicing variants in the OPA1 gene. Hum. Genet. 109, 584-591. doi: 10.1007/s00439-001-0633-y
52. Delettre, C., Lenaers, G., Griffoin, J. M., Gigarel, N., Lorenzo, C., Belenguer, P., et al. (2000). Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat. Genet. 26, 207-210. doi: 10.1038/79936
53. De Sandre-Giovannoli, A., Chaouch, M., Boccaccio, I., Bernard, R., Delague, V., Grid, D., et al. (2003). Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and splicing mutations. J. Med. Genet. 40:e87. doi: 10.1136/jmg.40.7.e87
54. Detmer, S. A., and Chan, D. C. (2007). Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J. Cell Biol. 176, 405-414. doi: 10.1083/jcb.200611080
55. Detmer, S. A., Velde, C. V., Cleveland, D. W., and Chan, D. C. (2008). Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Hum. Mol. Genet. 17, 367-375. doi: 10.1093/hmg/ddm314
56. DeVay, R. M., Dominguez-Ramirez, L., Lackner, L. L., Hoppins, S., Stahlberg, H., and Nunnari, J. (2009). Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. J. Cell Biol. 186, 793-803. doi: 10.1083/jcb.200906098
57. Diano, S., Liu, Z. W., Jeong, J. K., Dietrich, M. O., Ruan, H. B., Kim, E., et al. (2011). Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat. Med. 17, 1121-1127. doi: 10.1038/nm.2421
58. Dietrich, M. O., Liu, Z. W., and Horvath, T. L. (2013). Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155, 188-199. doi: 10.1016/j.cell.2013.09.004
59. Dohm, J. A., Lee, S. J., Hardwick, J. M., Hill, R. B., and Gittis, A. G. (2004). Cytosolic domain of the human mitochondrial fission protein fis1 adopts a TPR fold. Proteins Struct. Funct. Bioinformatics 54, 153-156. doi: 10.1002/prot.10524
60. Dyck, P. J., and Lambert, E. H. (1968). Lower motor and primary sensory neuron diseases with peroneal muscular atrophy: I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch. Neurol. 18, 603-618. doi: 10.1001/archneur.1968.00470360025002
61. Ehses, S., Raschke, I., Mancuso, G., Bernacchia, A., Geimer, S., Tondera, D., et al. (2009). Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J. Cell Biol. 187, 1023-1036. doi: 10.1083/jcb.200906084
62. Elias, C. F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R. S., Bjorbaek, C., et al. (1999). Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775-786. doi: 10.1016/S0896-6273(01)80035-0
63. Engelfried, K., Vorgerd, M., Hagedorn, M., Haas, G., Gilles, J., Epplen, J., et al. (2006). Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med. Genet. 7:53. doi: 10.1186/1471-2350-7-53
64. Eura, Y., Ishihara, N., Oka, T., and Mihara, K. (2006). Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function. J. Cell Sci. 119, 4913-4925. doi: 10.1242/jcs.03253
65. 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. J. Biochem. 134, 333-344. doi: 10.1093/jb/mvg150
66. Exner, N., Treske, B., Paquet, D., Holmstrom, K., Schiesling, C., Gispert, S., et al. (2007). Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J. Neurosci. 27, 12413-12418. doi: 10.1523/JNEUROSCI.0719-07.2007
67. Ferreira, I. L., Resende, R., Ferreiro, E., Rego, A. C., and Pereira, C. F. (2010). Multiple defects in energy metabolism in Alzheimer's disease. Curr. Drug Targets 11, 1193-1206. doi: 10.2174/1389450111007011193
68. Ferré, M., Amati-Bonneau, P., Tourmen, Y., Malthièry, Y., and Reynier, P. (2005). eOPA1: an online database for OPA1 mutations. Hum. Mutat. 25, 423-428. doi: 10.1002/humu.20161
69. Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G. V., Rudka, T., et al. (2006). OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177-189. doi: 10.1016/j.cell.2006.06.025
70. Friedman, J. R., Lackner, L. L., West, M., DiBenedetto, J. R., Nunnari, J., and Voeltz, G. K. (2011). ER tubules mark sites of mitochondrial division. Science 334, 358-362. doi: 10.1126/science.1207385
71. Gandre-Babbe, S., and van der Bliek, A. M. (2008). The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol. Biol. Cell. 19, 2402-2412. doi: 10.1091/mbc.E07-12-1287
72. Gao, A. W., Canto, C., and Houtkooper, R. H. (2014). Mitochondrial response to nutrient availability and its role in metabolic disease. EMBO Mol. Med. 6, 580-589. doi: 10.1002/emmm.201303782
73. Gegg, M. E., Cooper, J. M., Chau, K. Y., Rojo, M., Schapira, A. H., and Taanman, J. W. (2010). Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19, 4861-4870. doi: 10.1093/hmg/ddq419
74. Gomez-Lazaro, M., Bonekamp, N. A., Galindo, M. F., Jordan, J., and Schrader, M. (2008). 6-Hydroxydopamine (6-OHDA) induces Drp1-dependent mitochondrial fragmentation in SH-SY5Y cells. Free Radic. Biol. Med. 44, 1960-1969. doi: 10.1016/j.freeradbiomed.2008.03.009
75. Griparic, L., Kanazawa, T., and van der Bliek, A. M. (2007). Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J. Cell Biol. 178, 757-764. doi: 10.1083/jcb.200704112
76. Griparic, L., van der Wel, N. N., Orozco, I. J., Peters, P. J., and van der Bliek, A. M. (2004). Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J. Biol. Chem. 279, 18792-18798. doi: 10.1074/jbc.M400920200
77. Grunewald, A., Gegg, M. E., Taanman, J. W., King, R. H., Kock, N., Klein, C., et al. (2009). Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology. Exp. Neurol. 219, 266-273. doi: 10.1016/j.expneurol.2009.05.027
78. Hales, K. G., and Fuller, M. T. (1997). Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90, 121-129. doi: 10.1016/S0092-8674(00)80319-0
79. Harder, Z., Zunino, R., and McBride, H. (2004). Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340-345. doi: 10.1016/j.cub.2004.02.004
80. Hayashi, T., and Su, T. P. (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131, 596-610. doi: 10.1016/j.cell.2007.08.036
81. Head, B., Griparic, L., Amiri, M., Gandre-Babbe, S., and van der Bliek, A. M. (2009). Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J. Cell Biol. 187, 959-966. doi: 10.1083/jcb.200906083
82. Hernandez-Alvarez, M. I., Paz, J. C., Sebastian, D., Munoz, J. P., Liesa, M., Segales, J., et al. (2013). Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1. Antioxid. Redox Signal. 19, 366-378. doi: 10.1089/ars.2011.4269
83. Hill, J. W., Williams, K. W., Ye, C., Luo, J., Balthasar, N., Coppari, R., et al. (2008). Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J. Clin. Invest. 118, 1796-1805. doi: 10.1172/JCI32964
84. Hoozemans, J. J. M., Veerhuis, R., Van Haastert, E. S., Rozemuller, J. M., Baas, F., Eikelenboom, P., et al. (2005). The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol. 110, 165-172. doi: 10.1007/s00401-005-1038-0
85. Hoyt, C. (1980). Autosomal dominant optic atrophy. A spectrum of disability. Ophthalmology 87, 245-251. doi: 10.1016/S0161-6420(80)35247-0
86. Hudson, G., Amati-Bonneau, P., Blakely, E. L., Stewart, J. D., He, L., Schaefer, A. M., 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. doi: 10.1093/brain/awm272
87. Ibrahim, N., Bosch, M. A., Smart, J. L., Qiu, J., Rubinstein, M., Ronnekleiv, O. K., et al. (2003). Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144, 1331-1340. doi: 10.1210/en.2002-221033
88. Ingerman, E., Perkins, E. M., Marino, M., Mears, J. A., McCaffery, J. M., Hinshaw, J. E., et al. (2005). Dnm1 forms spirals that are structurally tailored to fit mitochondria. J. Cell Biol. 170, 1021-1027. doi: 10.1083/jcb.200506078
89. Ishihara, N., Eura, Y., and 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
90. Ishihara, N., Fujita, Y., Oka, T., and Mihara, K. (2006). Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J. 25, 2966-2977. doi: 10.1038/sj.emboj.7601184
91. Ishihara, N., Nomura, M., Jofuku, A., Kato, H., Suzuki, S. O., Masuda, K., et al. (2009). Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 11, 958-966. doi: 10.1038/ncb1907
92. Iwasawa, R., Mahul-Mellier, A. L., Datler, C., Pazarentzos, E., and Grimm, S. (2011). Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J. 30, 556-568. doi: 10.1038/emboj.2010.346
93. Jahani-Asl, A., Pilon-Larose, K., Xu, W., MacLaurin, J. G., Park, D. S., McBride, H. M., et al. (2011). The mitochondrial inner membrane GTPase, optic atrophy 1 (Opa1), restores mitochondrial morphology and promotes neuronal survival following excitotoxicity. J. Biol. Chem. 286, 4772-4782. doi: 10.1074/jbc.M110.167155
94. Jofuku, A., Ishihara, N., and Mihara, K. (2005). Analysis of functional domains of rat mitochondrial Fis1, the mitochondrial fission-stimulating protein. Biochem. Biophys. Res. Commun. 333, 650-659. doi: 10.1016/j.bbrc.2005.05.154
95. Johnston, P., Gaster, R., Smith, V., and Tripathi, R. (1979). A clinicopathologic study of autosomal dominant optic atrophy. Am. J. Ophthalmol. 88, 868-875. doi: 10.1016/0002-9394(79)90565-8
96. Johnston, R. L., Seller, M. J., Behnam, J. T., Burdon, M. A., and Spalton, D. J. (1999). Dominant optic atrophy: refining the clinical diagnostic criteria in light of genetic linkage studies. Ophthalmology 106, 123-128. doi: 10.1016/S0161-6420(99)90013-1
97. Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H., and Wakabayashi, I. (2001). Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 50, 2438-2443. doi: 10.2337/diabetes.50.11.2438
98. Karbowski, M., Neutzner, A., and Youle, R. J. (2007). The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J. Cell Biol. 178, 71-84. doi: 10.1083/jcb.200611064
99. Karren, M. A., Coonrod, E. M., Anderson, T. K., and Shaw, J. M. (2005). The role of Fis1p-Mdv1p interactions in mitochondrial fission complex assembly. J. Cell Biol. 171, 291-301. doi: 10.1083/jcb.200506158
100. Kijima, K., Numakura, C., Izumino, H., Umetsu, K., Nezu, A., Shiiki, T., et al. (2005). Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum. Genet. 116, 23-27. doi: 10.1007/s00439-004-1199-2
101. Kim, I., Rodriguez-Enriquez, S., and Lemasters, J. J. (2007). Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245-253. doi: 10.1016/j.abb.2007.03.034
102. Kim, J. Y., Hwang, J.-M., Ko, H. S., Seong, M.-W., Park, B.-J., and Park, S. S. (2005). Mitochondrial DNA content is decreased in autosomal dominant optic atrophy. Neurology 64, 966-972. doi: 10.1212/01.WNL.0000157282.76715.B1
103. Kjer, P., Jensen, O., and Klinken, L. (1983). Histopathology of eye, optic nerve and brain in a case of dominant optic atrophy. Acta Ophthalmol. 61, 300-312. doi: 10.1111/j.1755-3768.1983.tb01424.x
104. Koshiba, T., Detmer, S. A., Kaiser, J. T., Chen, H., McCaffery, J. M., and Chan, D. C. (2004). Structural basis of mitochondrial tethering by mitofusin complexes. Science 305, 858-862. doi: 10.1126/science.1099793
105. Lackner, L. L., Horner, J. S., and Nunnari, J. (2009). Mechanistic analysis of a dynamin effector. Science 325, 874-877. doi: 10.1126/science.1176921
106. Lawson, V. H., Graham, B. V., and Flanigan, K. M. (2005). Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65, 197-204. doi: 10.1212/01.wnl.0000168898.76071.70
107. Leboucher, G. P., Tsai, Y. C., Yang, M., Shaw, K. C., Zhou, M., Veenstra, T. D., et al. (2012). Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol. Cell. 47, 547-557. doi: 10.1016/j.molcel.2012.05.041
108. Lee, J. Y., Kapur, M., Li, M., Choi, M. C., Choi, S., Kim, H. J., et al. (2014). MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria. J. Cell Sci. 127, 4954-4963. doi: 10.1242/jcs.157321
109. Lee, S., Sterky, F. H., Mourier, A., Terzioglu, M., Cullheim, S., Olson, L., et al. (2012). Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons. Hum. Mol. Genet. 21, 4827-4835. doi: 10.1093/hmg/dds352
110. Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L., and Youle, R. J. (2004). Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, Opa1 in apoptosis. Mol. Biol. Cell. 15, 5001-5011. doi: 10.1091/mbc.E04-04-0294
111. Legesse-Miller, A., Massol, R. H., and Kirchhausen, T. (2003). Constriction and Dnm1p recruitment are distinct processes in mitochondrial fission. Mol. Biol. Cell. 14, 1953-1963. doi: 10.1091/mbc.E02-10-0657
112. Lelliott, C. J., Medina-Gomez, G., Petrovic, N., Kis, A., Feldmann, H. M., Bjursell, M., et al. (2006). Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol. 4:e369. doi: 10.1371/journal.pbio.0040369
113. Li, J., Li, Y., Jiao, J., Wang, J., Qin, D., and Li, P. (2014). Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis. Mol. Cell. Biol. 34, 1788-1799. doi: 10.1128/MCB.00774-13
114. Li, Z., Okamoto, K., Hayashi, Y., and Sheng, M. (2004). The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873-887. doi: 10.1016/j.cell.2004.11.003
115. Liesa, M., Borda-d'Agua, B., Medina-Gomez, G., Lelliott, C. J., Paz, J. C., Rojo, M., et al. (2008). Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta. PLoS ONE 3:e3613. doi: 10.1371/journal.pone.0003613
116. Liesa, M., and Shirihai, O. S. (2013). Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 17, 491-506. doi: 10.1016/j.cmet.2013.03.002
117. Loiseau, D., Chevrollier, A., Verny, C., Guillet, V., Gueguen, N., Pou de Crescenzo, M. A., et al. (2007). Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease. Ann. Neurol. 61, 315-323. doi: 10.1002/ana.21086
118. Lokireddy, S., Wijesoma, I. W., Teng, S., Bonala, S., Gluckman, P. D., McFarlane, C., et al. (2012). The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab. 16, 613-624. doi: 10.1016/j.cmet.2012.10.005
119. Long, L., Toda, C., Jeong, J. K., Horvath, T. L., and Diano, S. (2014). PPARgamma ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding. J. Clin. Invest. 124, 4017-4027. doi: 10.1172/JCI76220
120. Lopez, M., Lage, R., Saha, A. K., Perez-Tilve, D., Vazquez, M. J., Varela, L., et al. (2008). Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 7, 389-399. doi: 10.1016/j.cmet.2008.03.006
121. Lopez Del Amo, V., Seco-Cervera, M., Garcia-Gimenez, J. L., Whitworth, A. J., Pallardo, F. V., and Galindo, M. I. (2015). Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy. Hum. Mol. Genet. 24, 21-36. doi: 10.1093/hmg/ddu416
122. Loson, O. C., Song, Z., Chen, H., and Chan, D. C. (2013). Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol. Biol. Cell. 24, 659-667. doi: 10.1091/mbc.E12-10-0721
123. Luquet, S., Phillips, C. T., and Palmiter, R. D. (2007). NPY/AgRP neurons are not essential for feeding responses to glucoprivation. Peptides 28, 214-225. doi: 10.1016/j.peptides.2006.08.036
124. Lutz, A. K., Exner, N., Fett, M. E., Schlehe, J. S., Kloos, K., Lammermann, K., et al. (2009). Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J. Biol. Chem. 284, 22938-22951. doi: 10.1074/jbc.M109.035774
125. Mailloux, R. J., and Harper, M. E. (2011). Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic. Biol. Med. 51, 1106-1115. doi: 10.1016/j.freeradbiomed.2011.06.022
126. Martin, O. J., Lai, L., Soundarapandian, M. M., Leone, T. C., Zorzano, A., Keller, M. P., et al. (2014). A role for peroxisome proliferator-activated receptor gamma coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth. Circ. Res. 114, 626-636. doi: 10.1161/CIRCRESAHA.114.302562
127. Martorell-Riera, A., Segarra-Mondejar, M., Munoz, J. P., Ginet, V., Olloquequi, J., Perez-Clausell, J., et al. (2014). Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death. EMBO J. 33, 2388-2407. doi: 10.15252/embj.201488327
128. Mears, J. A., Lackner, L. L., Fang, S., Ingerman, E., Nunnari, J., and Hinshaw, J. E. (2011). Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat. Struct. Mol. Biol. 18, 20-26. doi: 10.1038/nsmb.1949
129. Meeusen, S., McCaffery, J. M., and Nunnari, J. (2004). Mitochondrial fusion intermediates revealed in vitro. Science 305, 1747-1752. doi: 10.1126/science.1100612
130. Misaka, T., Miyashita, T., and Kubo, Y. (2002). Primary structure of a dynamin-related mouse mitochondrial GTPase and its distribution in brain, subcellular localization, and effect on mitochondrial morphology. J. Biol. Chem. 277, 15834-15842. doi: 10.1074/jbc.M109260200
131. Mizuno, T. M., Kleopoulos, S. P., Bergen, H. T., Roberts, J. L., Priest, C. A., and Mobbs, C. V. (1998). Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47, 294-297. doi: 10.2337/diab.47.2.294
132. Mizuno, T. M., and Mobbs, C. V. (1999). Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814-817. doi: 10.1210/en.140.2.814
133. Mozdy, A. D., McCaffery, J. M., and Shaw, J. M. (2000). Dnm1p Gtpase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J. Cell Biol. 151, 367-380. doi: 10.1083/jcb.151.2.367
134. Munoz, J. P., Ivanova, S., Sanchez-Wandelmer, J., Martinez-Cristobal, P., Noguera, E., Sancho, A., et al. (2013). Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J. 32, 2348-2361. doi: 10.1038/emboj.2013.168
135. Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., et al. (2001). A role for ghrelin in the central regulation of feeding. Nature 409, 194-198. doi: 10.1038/35051587
136. Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D.-F., Gautier, C. A., Shen, J., et al. (2010). PINK1 is selectively stabilized on impaired mitochondria to activate parkin. PLoS Biol. 8:e1000298. doi: 10.1371/journal.pbio.1000298
137. Nelis, E., Erdem, S., Van den Bergh, P. Y. K., Belpaire-Dethiou, M.-C., Ceuterick, C., Van Gerwen, V., et al. (2002). Mutations in GDAP1. Neurology 59, 1865-1872. doi: 10.1212/01.WNL.0000036272.36047.54
138. Niemann, A., Ruegg, M., La Padula, V., Schenone, A., and Suter, U. (2005). Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J. Cell Biol. 170, 1067-1078. doi: 10.1083/jcb.200507087
139. Nunnari, J., Marshall, W., Straight, A., Murray, A., Sedat, J., and Walter, P. (1997). Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA. Mol. Biol. Cell 8, 1233-1242. doi: 10.1091/mbc.8.7.1233
140. Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P., 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, 7743-7746. doi: 10.1074/jbc.C200677200
141. Olichon, A., Elachouri, G., Baricault, L., Delettre, C., Belenguer, P., and Lenaers, G. (2007). OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis. Cell Death Differ. 14, 682-692. doi: 10.1038/sj.cdd.4402048
142. Olichon, A., Emorine, L. J., Descoins, E., Pelloquin, L., Brichese, L., Gas, N., et al. (2002). The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett. 523, 171-176. doi: 10.1016/S0014-5793(02)02985-X
143. Olichon, A., Guillou, E., Delettre, C., Landes, T., Arnauné-Pelloquin, L., Emorine, L. J., et al. (2006). Mitochondrial dynamics and disease, OPA1. Biochim. Biophys. Acta 1763, 500-509. doi: 10.1016/j.bbamcr.2006.04.003
144. Ollmann, M. M., Wilson, B. D., Yang, Y. K., Kerns, J. A., Chen, Y., Gantz, I., et al. (1997). Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135-138. doi: 10.1126/science.278.5335.135
145. Otera, H., Wang, C., Cleland, M. M., Setoguchi, K., Yokota, S., Youle, R. J., 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. doi: 10.1083/jcb.201007152
146. Ozcan, L., Ergin, A. S., Lu, A., Chung, J., Sarkar, S., Nie, D., et al. (2009). Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35-51. doi: 10.1016/j.cmet.2008.12.004
147. 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. doi: 10.1038/embor.2011.54
148. Panov, A. V., Gutekunst, C. A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., et al. (2002). Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat. Neurosci. 5, 731-736. doi: 10.1038/nn884
149. Papanicolaou, K. N., Khairallah, R. J., Ngoh, G. A., Chikando, A., Luptak, I., O'Shea, K. M., et al. (2011). Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol. Cell. Biol. 31, 1309-1328.
150. Papanicolaou, K. N., Ngoh, G. A., Dabkowski, E. R., O'Connell, K. A., Ribeiro, R. F. Jr., Stanley, W. C., et al. (2012). Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am. J. Physiol. Heart Circ. Physiol. 302, H167-H179.
151. Park, Y. Y., and Cho, H. (2012). Mitofusin 1 is degraded at G2/M phase through ubiquitylation by MARCH5. Cell Div. 7, 25. doi: 10.1186/1747-1028-7-25
152. Park, Y. Y., Lee, S., Karbowski, M., Neutzner, A., Youle, R. J., and Cho, H. (2010). Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1. J. Cell Sci. 123, 619-626. doi: 10.1242/jcs.061481
153. Parone, P. A., Da Cruz, S., Tondera, D., Mattenberger, Y., James, D. I., Maechler, P., et al. (2008). Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3:e3257. doi: 10.1371/journal.pone.0003257
154. Parton, L. E., Ye, C. P., Coppari, R., Enriori, P. J., Choi, B., Zhang, C. Y., et al. (2007). Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228-232. doi: 10.1038/nature06098
155. Pesch, U. E. A., Leo-Kottler, B., Mayer, S., Jurklies, B., Kellner, U., Apfelstedt-Sylla, E., et al. (2001). OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance. Hum. Mol. Genet. 10, 1359-1368. doi: 10.1093/hmg/10.13.1359
156. Pham, A. H., Meng, S., Chu, Q. N., and Chan, D. C. (2012). Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit. Hum. Mol. Genet. 21, 4817-4826. doi: 10.1093/hmg/dds311
157. Pich, S., Bach, D., Briones, P., Liesa, M., Camps, M., Testar, X., 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. doi: 10.1093/hmg/ddi149
158. Pickrell, A. M., and Youle, R. J. (2015). The roles of PINK1, parkin, and mitochondrial fidelity in parkinson's disease. Neuron 85, 257-273. doi: 10.1016/j.neuron.2014.12.007
159. Pitts, K. R., Yoon, Y., Krueger, E. W., and McNiven, M. A. (1999). The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol. Biol. Cell. 10, 4403-4417. doi: 10.1091/mbc.10.12.4403
160. Poggioli, R., Vergoni, A. V., and Bertolini, A. (1986). ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists. Peptides 7, 843-848. doi: 10.1016/0196-9781(86)90104-X
161. Poole, A. C., Thomas, R. E., Yu, S., Vincow, E. S., and Pallanck, L. (2010). The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS ONE 5:e10054. doi: 10.1371/journal.pone.0010054
162. Poston, C. N., Krishnan, S. C., and Bazemore-Walker, C. R. (2013). In-depth proteomic analysis of mammalian mitochondria-associated membranes (MAM). J. Proteomics 79, 219-230. doi: 10.1016/j.jprot.2012.12.018
163. Quiros, P. M., Ramsay, A. J., Sala, D., Fernandez-Vizarra, E., Rodriguez, F., Peinado, J. R., et al. (2012). Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J. 31, 2117-2133. doi: 10.1038/emboj.2012.70
164. Reddy, P. H., Reddy, T. P., Manczak, M., Calkins, M. J., Shirendeb, U., and Mao, P. (2011). Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res. Rev. 67, 103-118. doi: 10.1016/j.brainresrev.2010.11.004
165. Rojo, M., Legros, F., Chateau, D., and Lombès, A. (2002). Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J. Cell Sci. 115, 1663-1674.
166. Roseberry, A. G., Liu, H., Jackson, A. C., Cai, X., and Friedman, J. M. (2004). Neuropeptide Y-mediated inhibition of proopiomelanocortin neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice. Neuron 41, 711-722. doi: 10.1016/S0896-6273(04)00074-1
167. Rui, Y., Tiwari, P., Xie, Z., and Zheng, J. Q. (2006). Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J. Neurosci. 26, 10480-10487. doi: 10.1523/JNEUROSCI.3231-06.2006
168. Sandebring, A., Thomas, K. J., Beilina, A., van der Brug, M., Cleland, M. M., Ahmad, R., et al. (2009). Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS ONE 4:e5701. doi: 10.1371/journal.pone.0005701
169. Santel, A., Frank, S., Gaume, B., Herrler, M., Youle, R. J., and Fuller, M. T. (2003). Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J. Cell Sci. 116, 2763-2774. doi: 10.1242/jcs.00479
170. Sarzi, E., Angebault, C., Seveno, M., Gueguen, N., Chaix, B., Bielicki, G., et al. (2012). The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse. Brain 135, 3599-3613. doi: 10.1093/brain/aws303
171. Satoh, M., Hamamoto, T., Seo, N., Kagawa, Y., and Endo, H. (2003). Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria. Biochem. Biophys. Res. Commun. 300, 482-493. doi: 10.1016/S0006-291X(02)02874-7
172. Scarpulla, R. C., Vega, R. B., and Kelly, D. P. (2012). Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459-466. doi: 10.1016/j.tem.2012.06.006
173. Schapira, A. H., Bezard, E., Brotchie, J., Calon, F., Collingridge, G. L., Ferger, B., et al. (2006). Novel pharmacological targets for the treatment of Parkinson's disease. Nat. Rev. Drug Discov. 5, 845-854. doi: 10.1038/nrd2087
174. Schapira, A. H., Olanow, C. W., Greenamyre, J. T., and Bezard, E. (2014). Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. Lancet 384, 545-555. doi: 10.1016/S0140-6736(14)61010-2
175. Schneeberger, M., Dietrich, M. O., Sebastian, D., Imbernon, M., Castano, C., Garcia, A., et al. (2013). Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172-187. doi: 10.1016/j.cell.2013.09.003
176. Schneeberger, M., Gomis, R., and Claret, M. (2014). Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J. Endocrinol. 220, T25-T46. doi: 10.1530/joe-13-0398
177. Schon, E. A., and Area-Gomez, E. (2010). Is Alzheimer's disease a disorder of mitochondria-associated membranes? J. Alzheimer's Dis. 20, S281-S292. doi: 10.3233/JAD-2010-100495
178. Schwartz, M. W., Baskin, D. G., Bukowski, T. R., Kuijper, J. L., Foster, D., Lasser, G., et al. (1996). Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45, 531-535. doi: 10.2337/diab.45.4.531
179. Schwartz, M. W., Seeley, R. J., Woods, S. C., Weigle, D. S., Campfield, L. A., Burn, P., et al. (1997). Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119-2123. doi: 10.2337/diab.46.12.2119
180. Sebastian, D., Hernandez-Alvarez, M. I., Segales, J., Sorianello, E., Munoz, J. P., Sala, D., et al. (2012). Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc. Natl. Acad. Sci. U.S.A. 109, 5523-5528. doi: 10.1073/pnas.1108220109
181. Senderek, J., Bergmann, C., Ramaekers, V. T., Nelis, E., Bernert, G., Makowski, A., et al. (2003). Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 126, 642-649. doi: 10.1093/brain/awg068
182. Sevilla, T., Cuesta, A., Chumillas, M. J., Mayordomo, F., Pedrola, L., Palau, F., et al. (2003). Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene. Brain 126, 2023-2033. doi: 10.1093/brain/awg202
183. Shirendeb, U., Reddy, A. P., Manczak, M., Calkins, M. J., Mao, P., Tagle, D. A., et al. (2011). Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Hum. Mol. Genet. 20, 1438-1455. doi: 10.1093/hmg/ddr024
184. Simmen, T., Aslan, J. E., Blagoveshchenskaya, A. D., Thomas, L., Wan, L., Xiang, Y., et al. (2005). PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J. 24, 717-729. doi: 10.1038/sj.emboj.7600559
185. Simpson, J. C., Wellenreuther, R., Poustka, A., Pepperkok, R., and Wiemann, S. (2000). Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. EMBO Rep. 1, 287-292. doi: 10.1093/embo-reports/kvd058
186. Skre, H. (1974). Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin. Genet. 6, 98-118. doi: 10.1111/j.1399-0004.1974.tb00638.x
187. Smith, M. A., Hisadome, K., Al-Qassab, H., Heffron, H., Withers, D. J., and Ashford, M. L. (2007). Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances. J. Physiol. 578(Pt 2), 425-38. doi: 10.1113/jphysiol.2006.119479
188. Song, W., Chen, J., Petrilli, A., Liot, G., Klinglmayr, E., Zhou, Y., et al. (2011). Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat. Med. 17, 377-382. doi: 10.1038/nm.2313
189. Song, Z., Chen, H., Fiket, M., Alexander, C., and Chan, D. C. (2007). OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J. Cell Biol. 178, 749-755. doi: 10.1083/jcb.200704110
190. Sorianello, E., Soriano, F. X., Fernandez-Pascual, S., Sancho, A., Naon, D., Vila-Caballer, M., et al. (2012). The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells. Cardiovasc. Res. 94, 38-47. doi: 10.1093/cvr/cvs006
191. Soriano, F. X., Liesa, M., Bach, D., Chan, D. C., Palacin, M., and Zorzano, A. (2006). Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 55, 1783-1791. doi: 10.2337/db05-0509
192. Stephens, T. W., Basinski, M., Bristow, P. K., Bue-Valleskey, J. M., Burgett, S. G., Craft, L., et al. (1995). The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530-532. doi: 10.1038/377530a0
193. Stojanovski, D., Koutsopoulos, O. S., Okamoto, K., and Ryan, M. T. (2004). Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J. Cell Sci. 117, 1201-1210. doi: 10.1242/jcs.01058
194. Stone, S. J., and Vance, J. E. (2000). Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J. Biol. Chem. 275, 34534-34540. doi: 10.1074/jbc.M002865200
195. Sugiura, A., Nagashima, S., Tokuyama, T., Amo, T., Matsuki, Y., Ishido, S., et al. (2013). MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol. Cell. 51, 20-34. doi: 10.1016/j.molcel.2013.04.023
196. Supnet, C., and Bezprozvanny, I. (2010). Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease. J. Alzheimer's Dis. 20, S487-S498. doi: 10.3233/JAD-2010-100306
197. Sutendra, G., Dromparis, P., Wright, P., Bonnet, S., Haromy, A., Hao, Z., et al. (2011). The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci. Transl. Med. 3:88ra55. doi: 10.1126/scitranslmed.3002194
198. Suter, U., and Scherer, S. S. (2003). Disease mechanisms in inherited neuropathies. Nat. Rev. Neurosci. 4, 714-726. doi: 10.1038/nrn1196
199. Suzuki, M., Jeong, S.-Y., Karbowski, M., Youle, R. J., and Tjandra, N. (2003). The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. J. Mol. Biol. 334, 445-458. doi: 10.1016/j.jmb.2003.09.064
200. Szabadkai, G., Bianchi, K., Varnai, P., De Stefani, D., Wieckowski, M. R., Cavagna, D., et al. (2006). Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J. Cell Biol. 175, 901-911. doi: 10.1083/jcb.200608073
201. Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taanman, J. W., Cooper, J. M., and Schapira, A. H. (1999). Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Ann. Neurol. 45, 25-32.
202. Taguchi, N., Ishihara, N., Jofuku, A., Oka, T., and Mihara, K. (2007). Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 282, 11521-11529. doi: 10.1074/jbc.M607279200
203. Tanaka, A., Cleland, M. M., Xu, S., Narendra, D. P., Suen, D. F., Karbowski, M., et al. (2010). Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367-1380. doi: 10.1083/jcb.201007013
204. Thornton, J. E., Cheung, C. C., Clifton, D. K., and Steiner, R. A. (1997). Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138, 5063-5066. doi: 10.1210/endo.138.11.5651
205. Tondera, D., Grandemange, S., Jourdain, A., Karbowski, M., Mattenberger, Y., Herzig, S., et al. (2009). SlP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 28, 1589-1600. doi: 10.1038/emboj.2009.89
206. Twig, G., Elorza, A., Molina, A. J., Mohamed, H., Wikstrom, J. D., Walzer, G., et al. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433-446. doi: 10.1038/sj.emboj.7601963
207. Vance, J. E. (1990). Phospholipid synthesis in a membrane fraction associated with mitochondria. J. Biol. Chem. 265, 7248-7256.
208. Van Der Bliek, A. M. (1999). Functional diversity in the dynamin family. Trends Cell Biol. 9, 96-102. doi: 10.1016/S0962-8924(98)01490-1
209. Verhoeven, K., Claeys, K. G., Züchner, S., Schröder, J. M., Weis, J., Ceuterick, C., et al. (2006). MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129, 2093-2102. doi: 10.1093/brain/awl126
210. Vong, L., Ye, C., Yang, Z., Choi, B., Chua, S. Jr., and Lowell, B. B. (2011). Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142-154. doi: 10.1016/j.neuron.2011.05.028
211. Votruba, M., Fitzke, F. W., Holder, G. E., Carter, A., Bhattacharya, S. S., and Moore, A. T. (1998). Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy. Arch. Ophthalmol. 116, 351-358. doi: 10.1001/archopht.116.3.351
212. Wang, H., Lim, P. J., Karbowski, M., and Monteiro, M. J. (2009b). Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum. Mol. Genet. 18, 737-752. doi: 10.1093/hmg/ddn404
213. Wang, H., Song, P., Du, L., Tian, W., Yue, W., Liu, M., et al. (2011). Parkin ubiquitinates Drp1 for proteasome-dependent degradation. J. Biol. Chem. 286, 11649-11658. doi: 10.1074/jbc.M110.144238
214. Wang, Q., Liu, C., Uchida, A., Chuang, J. C., Walker, A., Liu, T., et al. (2014). Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Mol Metab. 3, 64-72. doi: 10.1016/j.molmet.2013.10.001
215. Wang, X., Su, B., Lee, H. G., Li, X., Perry, G., Smith, M. A., et al. (2009a). Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J. Neurosci. 29, 9090-9103. doi: 10.1523/JNEUROSCI.1357-09.2009
216. Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., et al. (2008). Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc. Natl. Acad. Sci. U.S.A. 105, 19318-19323. doi: 10.1073/pnas.0804871105
217. Wasiak, S., Zunino, R., and McBride, H. M. (2007). Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J. Cell Biol. 177, 439-450. doi: 10.1083/jcb.200610042
218. Willesen, M. G., Kristensen, P., and Romer, J. (1999). Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306-316. doi: 10.1159/000054491
219. Williams, P. A., Morgan, J. E., and Votruba, M. (2010). Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy. Brain 133, 2942-2951. doi: 10.1093/brain/awq218
220. Wirth, M. M., Olszewski, P. K., Yu, C., Levine, A. S., and Giraudo, S. Q. (2001). Paraventricular hypothalamic alpha-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects. Peptides 22, 129-134. doi: 10.1016/S0196-9781(00)00367-3
221. Yaffe, M. P. (1999). The machinery of mitochondrial inheritance and behavior. Science 283, 1493-1497. doi: 10.1126/science.283.5407.1493
222. Yang, Y., Atasoy, D., Su, H. H., and Sternson, S. M. (2011). Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992-1003. doi: 10.1016/j.cell.2011.07.039
223. Yoon, Y., Krueger, E. W., Oswald, B. J., and McNiven, M. A. (2003). The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol. Cell. Biol. 23, 5409-5420. doi: 10.1128/MCB.23.15.5409-5420.2003
224. Yue, W., Chen, Z., Liu, H., Yan, C., Chen, M., Feng, D., et al. (2014). A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res. 24, 482-496. doi: 10.1038/cr.2014.20
225. Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., and Cai, D. (2008). Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61-73. doi: 10.1016/j.cell.2008.07.043
226. Zhu, D., Kennerson, M. L., Walizada, G., Züchner, S., Vance, J. M., and Nicholson, G. A. (2005). Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 65, 496-497. doi: 10.1212/01.wnl.0000171345.62270.29
227. Zhu, X. H., Qiao, H., Du, F., Xiong, Q., Liu, X., Zhang, X., et al. (2012). Quantitative imaging of energy expenditure in human brain. Neuroimage 60, 2107-2117. doi: 10.1016/j.neuroimage.2012.02.013
228. Ziviani, E., Tao, R. N., and Whitworth, A. J. (2010). Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc. Natl. Acad. Sci. U.S.A. 107, 5018-5023. doi: 10.1073/pnas.0913485107
229. Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., et al. (2004). Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 36, 449-451. doi: 10.1038/ng1341
230. Zunino, R., Braschi, E., Xu, L., and McBride, H. M. (2009). Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J. Biol. Chem. 284, 17783-17795. doi: 10.1074/jbc.M901902200