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Mitophagy: Therapeutic Potentials for Liver Disease and Beyond

  • Received : 2014.11.21
  • Accepted : 2014.12.29
  • Published : 2014.12.31

Abstract

Mitochondrial integrity is critical for maintaining proper cellular functions. A key aspect of regulating mitochondrial homeostasis is removing damaged mitochondria through autophagy, a process called mitophagy. Autophagy dysfunction in various disease states can inactivate mitophagy and cause cell death, and defects in mitophagy are becoming increasingly recognized in a wide range of diseases from liver injuries to neurodegenerative diseases. Here we highlight our current knowledge on the mechanisms of mitophagy, and discuss how alterations in mitophagy contribute to disease pathogenesis. We also discuss mitochondrial dynamics and potential interactions between mitochondrial fusion, fission and mitophagy.

Keywords

References

  1. Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., Bause, A., Li, Y., Stommel, J.M., Dell'antonio, G., Mauther, J., Tonon, G., Haigis, M., Shirihai, O.S., Doglioni, C., Bardeesy, N. and Kimmelman, A.C. (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev., 25, 717-729. https://doi.org/10.1101/gad.2016111
  2. Guo, J.Y., Chen, H.Y., Mathew, R., Fan, J., Strohecker, A.M., Karsli-Uzunbas, G., Kamphorst, J.J., Chen, G., Lemons, J.M., Karantza, V., Coller, H.A., Dipaola, R.S., Gelinas, C., Rabinowitz, J.D. and White, E. (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev., 25, 460-470. https://doi.org/10.1101/gad.2016311
  3. White, E. (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer, 12, 401-410. https://doi.org/10.1038/nrc3262
  4. De Duve, C. and Wattiaux, R. (1966) Functions of lysosomes. Annu. Rev. Physiol., 28, 435-492. https://doi.org/10.1146/annurev.ph.28.030166.002251
  5. Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., Eishi, Y., Hino, O., Tanaka, K. and Mizushima, N. (2011) Autophagy-deficient mice develop multiple liver tumors. Genes Dev., 25, 795-800. https://doi.org/10.1101/gad.2016211
  6. Menzies, R.A. and Gold, P.H. (1971) The turnover of mitochondria in a variety of tissues of young adult and aged rats. J. Biol. Chem., 246, 2425-2429.
  7. Kim, I. and Lemasters, J.J. (2011) Mitophagy selectively degrades individual damaged mitochondria after photoirradiation. Antioxid. Redox Signaling, 14, 1919-1928. https://doi.org/10.1089/ars.2010.3768
  8. Kim, I., Rodriguez-Enriquez, S. and Lemasters, J.J. (2007) Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys., 462, 245-253. https://doi.org/10.1016/j.abb.2007.03.034
  9. Kim, J.S., Wang, J.H. and Lemasters, J.J. (2012) Mitochondrial permeability transition in rat hepatocytes after anoxia/ reoxygenation: role of $Ca^{2+}$-dependent mitochondrial formation of reactive oxygen species. Am. J. Physiol., 302, G723-731. https://doi.org/10.1152/ajpcell.00202.2011
  10. Kim, E.H. and Choi, K.S. (2008) A critical role of superoxide anion in selenite-induced mitophagic cell death. Autophagy, 4, 76-78. https://doi.org/10.4161/auto.5119
  11. Narendra, D., Tanaka, A., Suen, D.F. and Youle, R.J. (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol., 183, 795-803. https://doi.org/10.1083/jcb.200809125
  12. Kanki, T., Wang, K., Cao, Y., Baba, M. and Klionsky, D.J. (2009) Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev. Cell, 17, 98-109. https://doi.org/10.1016/j.devcel.2009.06.014
  13. Liu, L., Feng, D., Chen, G., Chen, M., Zheng, Q., Song, P., Ma, Q., Zhu, C., Wang, R., Qi, W., Huang, L., Xue, P., Li, B., Wang, X., Jin, H., Wang, J., Yang, F., Liu, P., Zhu, Y., Sui, S. and Chen, Q. (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol., 14, 177-185. https://doi.org/10.1038/ncb2422
  14. Wu, W., Tian, W., Hu, Z., Chen, G., Huang, L., Li, W., Zhang, C., Liu, L., Zhu, Y., Zhang, X., Li, L., Zhang, L., Sui, S., Zhao, B. and Feng, D. (2014) ULK2 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep., 15, 566-575. https://doi.org/10.1002/embr.201438501
  15. Sandoval, H., Thiagarajan, P., Dasgupta, S.K., Schumacher, A., Prchal, J.T., Chen, M. and Wang, J. (2008) Essential role for Nix in autophagic maturation of erythroid cells. Nature, 454, 232-235. https://doi.org/10.1038/nature07006
  16. 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. https://doi.org/10.1093/hmg/ddq419
  17. Narendra, D., Tanaka, A., Suen, D.F. and Youle, R.J. (2009) Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy, 5, 706-708. https://doi.org/10.4161/auto.5.5.8505
  18. Bingol, B., Tea, J.S., Phu, L., Reichelt, M., Bakalarski, C.E., Song, Q., Foreman, O., Kirkpatrick, D.S. and Sheng, M. (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature, 510, 370-375. https://doi.org/10.1038/nature13418
  19. Hara, Y., Yanatori, I., Ikeda, M., Kiyokage, E., Nishina, S., Tomiyama, Y., Toida, K., Kishi, F., Kato, N., Imamura, M., Chayama, K. and Hino, K. (2014) Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. Am. J. Pathol., 184, 3026-3039. https://doi.org/10.1016/j.ajpath.2014.07.024
  20. Ding, W.X., Ni, H.M., Li, M., Liao, Y., Chen, X., Stolz, D.B., Dorn, G.W. and Yin, X.M. (2010) Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J. Biol. Chem., 285, 27879-27890. https://doi.org/10.1074/jbc.M110.119537
  21. Hamacher-Brady, A., Brady, N.R., Logue, S.E., Sayen, M.R., Jinno, M., Kirshenbaum, L.A., Gottlieb, R.A. and Gustafsson, A.B. (2007) Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ., 14, 146-157. https://doi.org/10.1038/sj.cdd.4401936
  22. Czaja, M.J., Ding, W.X., Donohue, T.M., Friedman, S.L., Kim, J.S., Komatsu, M., Lemasters, J.J., Lemoine, A., Lin, J.D., Ou, J.H., Perlmutter, D.H., Randall, G., Ray, R.B., Tsung, A. and Yin, X.M. (2013) Functions of autophagy in normal and diseased liver. Autophagy, 9, 1131-1158. https://doi.org/10.4161/auto.25063
  23. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E.L., Mizushima, N., Ohsumi, Y., Cattoretti, G. and Levine, B. (2003) Promotion of turmorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest., 112, 1809-1820. https://doi.org/10.1172/JCI20039
  24. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M. and Czaja, M.J. (2009) Autophagy regulates lipid metabolism. Nature, 458, 1131-1135. https://doi.org/10.1038/nature07976
  25. Koga, H., Kaushik, S. and Cuervo, A.M. (2010) Altered lipid content inhibits autophagic vesicular fusion. FASEB J., 24, 3052-3065. https://doi.org/10.1096/fj.09-144519
  26. Harada, M., Hanada, S., Toivola, D.M., Ghori, N. and Omary, M.B. (2008) Autophagy activation by rapamycin elimates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation. Hepatology, 47, 2026-2035. https://doi.org/10.1002/hep.22294
  27. Ni, H.M., Bockus, A., Boggess, N., Jaeschke, H. and Ding, W.X. (2012) Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology, 55, 222-232. https://doi.org/10.1002/hep.24690
  28. Bond, J.M., Herman, B. and Lemasters, J.J. (1991) Protection by acidotic pH against anoxia/reoxygenation injury to rat neonatal cardiac myocytes. Biochem. Biophys. Res. Commun., 179, 798-803. https://doi.org/10.1016/0006-291X(91)91887-I
  29. Currin, R.T., Gores, G.J., Thurman, R.G. and Lemasters, J.J. (1991) Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox. FASEB J., 5, 207-210. https://doi.org/10.1096/fasebj.5.2.2004664
  30. Piper, H.M. (1989) Energy deficiency, calcium overload or oxidative stress: possible causes of irreversible ischemic myocardial injury. Klin. Wochenschr., 67, 465-476. https://doi.org/10.1007/BF01721672
  31. Kim, J.S., Qian, T. and Lemasters, J.J. (2003) Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes. Gastroenterology, 124, 494-503. https://doi.org/10.1053/gast.2003.50059
  32. Nishimura, Y., Romer, L.H. and Lemasters, J.J. (1998) Mitochondrial dysfunction and cytoskeletal disruption during chemical hypoxia to cultured rat hepatic sinusoidal endothelial cells: the pH paradox and cytoprotection by glucose, acidotic pH, and glycine. Hepatology, 27, 1039-1049. https://doi.org/10.1002/hep.510270420
  33. Kim, J.S., Nitta, T., Mohuczy, D., O'Malley, K.A., Moldawer, L.L., Dunn. W.A. and Behrns, K.E. (2008) Impaired autophagy: A mechanism of mitochondrial dysfunction in anoxic rat hepatocytes. Hepatology, 47, 1725-1736. https://doi.org/10.1002/hep.22187
  34. Wang, J.H., Behrns, K.E., Leeuwenburgh, C. and Kim, J.S. (2012) Critical role of autophagy in ischemia/reperfusion injury to aged livers. Autophagy, 8, 140-141. https://doi.org/10.4161/auto.8.1.18391
  35. Tsunemi, T., Ashe, T.D., Morrison, B.E., Soriano, K.R., Au, J., Roque, R.A., Lazarowski, E.R., Damian, V.A., Masliah, E. and La Spada, A.R. (2012) PGC-$1{\alpha}$ rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med., 4, 142ra97.
  36. Cortes, C.J., Miranda, H.C., Frankowski, H., Batlevi, Y., Young, J.E., Le, A., Ivanov, N., Sopher, B.L., Carromeu, C., Muotri, A.R., Garden, G.A. and La Spada, A.R. (2014) Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat. Neurosci., 17, 1180-1189. https://doi.org/10.1038/nn.3787
  37. Perlmutter, D.H. (2009) Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ., 16, 39-45. https://doi.org/10.1038/cdd.2008.103
  38. Kamimoto, T., Shoji, S., Hidvegi, T., Mizushima, N., Umebayashi, K., Perlmutter, D.H. and Yoshimori, T. (2006) Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J. Biol. Chem., 281, 4467-4476. https://doi.org/10.1074/jbc.M509409200
  39. Kruse, K.B., Brodsky, J.L. and McCracken, A.A. (2006) Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol. Biol. Cell, 17, 203-212.
  40. Hidvegi, T., Ewing, M., Hale, P., Dippold, C., Beckett, C., Kemp, C., Maurice, N., Mukherijee, A., Goldbach, C., Watkins, S., Michalopoulos, G. and Perlmutter, D.H. (2010) An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science, 329, 229-232. https://doi.org/10.1126/science.1190354
  41. Pastore, N., Blomenkamp, K., Annunziata, F., Piccolo, P., Mithbaokar, P., Maria Sepe, R., Vetrini, F., Palmer, D., Ng, P., Polishchuk, E., Iacobacci, S., Polishchuk, R., Teckman, J., Ballabio, A. and Brunetti-Pierri, N. (2013) Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency. EMBO Mol. Med., 5, 397-412. https://doi.org/10.1002/emmm.201202046
  42. Teckman, J.H., An, J.K., Blomenkamp, K., Schmidt, B. and Perlmutter, D. (2004) Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am. J. Physiol., 286, G851-862.
  43. Song, Z., Ghochani, M., McCaffery, J.M., Frey, T.G. and Chan, D.C. (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol. Biol. Cell, 20, 3525-3532. https://doi.org/10.1091/mbc.E09-03-0252
  44. Meeusen, S., DeVay, R., Block, J., Cassidy-Stone, A., Wayson, S., McCaffery, J.M. and Nunnari, J. (2006) Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell, 127, 383-395. https://doi.org/10.1016/j.cell.2006.09.021
  45. de Brito, O.M. and Scorrano, L. (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature, 456, 605-610. https://doi.org/10.1038/nature07534
  46. Ono, T., Isobe, K., Nakada, K. and Hayashi, J.I. (2001) Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat. Genet., 28, 272-275. https://doi.org/10.1038/90116
  47. Twig, G., Elorza, A., Molina, A.J., Mohamed, H., Wikstrom, J.D., Walzer, G., Stiles, L., Haigh, S.E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B.F., Yuan, J., Deeney, J.T., Corkey, B.E. and Shirihai, O.S. (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J., 27, 433-446. https://doi.org/10.1038/sj.emboj.7601963
  48. Dagda, R.K., Cherra, S.J., Kulich, S.M., Tandon, A., Park, D. and Chu, C.T. (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem., 284, 13843-13855. https://doi.org/10.1074/jbc.M808515200
  49. Hamasaki, M., Furuta, N., Matsuda, A., Nezu, A., Yamamoto, A., Fujita, N., Oomori, H., Noda, T., Haraguchi, T., Hiraoka, Y., Amano, A. and Yoshimori, T. (2013) Autophagosomes form at ER-mitochondria contact sites. Nature, 495, 389-393. https://doi.org/10.1038/nature11910
  50. Hailey, D.W., Rambold, A.S., Satpute-Krishnan, P., Mitra, K., Sougrat, R., Kim, P.K. and Lippincott-Schwartz, J. (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell, 141, 656-667. https://doi.org/10.1016/j.cell.2010.04.009
  51. Chen, Y. and Dorn, G.W. (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science, 340, 471-475. https://doi.org/10.1126/science.1231031
  52. Verhoeven, K., Claeys, K.G., Zuchner, S., Schroder, J.M., Weis, J., Ceuterick, C., Jordanova, A., Nelis, E., De Vriendt, E., Van Hul, M., Seeman, P., Mazanec, R., Saifi, G.M., Szigeti, K., Mancias, P., Butler, I.J., Kochanski, A., Ryniewicz, B., De Bleecker, J., Van den Bergh, P., Verellen, C., Van Coster, R., Goemans, N., Auer-Grumbach, M., Robberecht, W., Milic Rasic, V., Nevo, Y., Tournev, I., Guergueltcheva, V., Roelens, F., Vieregge, P., Vinci, P., Moreno, M.T., Christen, H.J., Shy, M.E., Lupski, J.R., Vance, J.M., De Jonghe, P. and Timmerman, V. (2006) MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. J. Neurol., 129, 2093-2102.
  53. Chung, K.W., Kim, S.B., Park, K.D., Choi, K.G., Lee, J.H., Eun, H.W., Suh, J.S., Hwang, J.H., Kim, W.K., Seo, B.C., Kim, S.H., Son, I.H., Kim, S.M., Sunwoo, I.N. and Choi, B.O. (2006) Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. J. Neurol., 129, 2103-2118.
  54. Bach, D., Naon, D., Pich, S., Soriano, F.X., Vega, N., Rieusset, J., Laville, M., Guillet, C., Boirie, Y., Wallberg-Henriksson, H., Manco, M., Calvani, M., Castagneto, M., Palacin, M., Mingrone, G., Zierath, J.R., Vidal, H. and Zorzano, A. (2005) Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes, 54, 2685-2693. https://doi.org/10.2337/diabetes.54.9.2685
  55. Hernandez-Alvarez, M.I., Thabit, H., Burns, N., Shah, S., Brema, I., Hatunic, M., Finucane, F., Liesa, M., Chiellini, C., Nano, D., Zorzano, A. and Nolan, J.J. (2010) Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1{alpha}/Mitofusin-2 regulatory pathway in response to physical activity. Diabetes Care, 33, 645-651. https://doi.org/10.2337/dc09-1305
  56. Sebastian, D., Hernandez-Alvarez, M.I., Segales, J., Sorianello, E., Munoz, J.P., Sala, D., Waget, A., Liesa, M., Paz, J.C., Gopalacharyulu, P., Oresic, M., Pich, S., Burcelin, R., Palacín, M. and Zorzano, A. (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. https://doi.org/10.1073/pnas.1108220109
  57. Biel, T., Flores-Toro, J.A., Dean, J., Lee, M.H., Lee, S., Dunn, W., Zendejas, I., Behrns, K.E. and Kim, J.S. (2014) Mitofusin-2 is a novel target of sirtuin 1 that enhances autophagy and confers cytoprotection against ischemia/reperfusion injury in human and mouse livers. Hepatology, 60, 250A-251A.
  58. Yu, W., Sun, Y., Guo, S. and Lu, B. (2011) The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. Hum. Mol. Genet., 20, 3227-3240. https://doi.org/10.1093/hmg/ddr235
  59. Poole, A.C., Thomas, R.E., Andrews, L.A., McBride, H.M., Whitworth, A.J. and Pallanck, L.J. (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc. Natl. Acad. Sci. U.S.A., 105, 1638-1643. https://doi.org/10.1073/pnas.0709336105
  60. Kim, J.S., He, L. and Lemasters, J.J. (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem. Biophys. Res. Commun., 304, 463-470. https://doi.org/10.1016/S0006-291X(03)00618-1

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