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http://dx.doi.org/10.5487/TR.2014.30.4.243

Mitophagy: Therapeutic Potentials for Liver Disease and Beyond  

Lee, Sooyeon (Department of Surgery, University of Florida)
Kim, Jae-Sung (Department of Surgery, University of Florida)
Publication Information
Toxicological Research / v.30, no.4, 2014 , pp. 243-250 More about this Journal
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
Autophagy; Mitochondria; Mitophagy; Liver; Brain;
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1 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.   DOI   ScienceOn
2 White, E. (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer, 12, 401-410.   DOI   ScienceOn
3 De Duve, C. and Wattiaux, R. (1966) Functions of lysosomes. Annu. Rev. Physiol., 28, 435-492.   DOI   ScienceOn
4 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.   DOI   ScienceOn
5 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.   DOI   ScienceOn
6 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.   DOI   ScienceOn
7 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.   DOI
8 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.
9 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.   DOI   ScienceOn
10 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.   DOI   ScienceOn
11 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.   DOI   ScienceOn
12 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.   DOI   ScienceOn
13 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.   DOI   ScienceOn
14 Chen, Y. and Dorn, G.W. (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science, 340, 471-475.   DOI   ScienceOn
15 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.   DOI   ScienceOn
16 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.
17 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.   DOI   ScienceOn
18 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.   DOI
19 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.
20 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.   DOI   ScienceOn
21 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.   DOI   ScienceOn
22 de Brito, O.M. and Scorrano, L. (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature, 456, 605-610.   DOI   ScienceOn
23 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.   DOI   ScienceOn
24 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.   DOI   ScienceOn
25 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.   DOI   ScienceOn
26 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.   DOI   ScienceOn
27 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.   DOI
28 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.   DOI   ScienceOn
29 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.   DOI   ScienceOn
30 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.   DOI   ScienceOn
31 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.
32 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.   DOI   ScienceOn
33 Koga, H., Kaushik, S. and Cuervo, A.M. (2010) Altered lipid content inhibits autophagic vesicular fusion. FASEB J., 24, 3052-3065.   DOI   ScienceOn
34 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.   DOI   ScienceOn
35 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.   DOI   ScienceOn
36 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.   DOI   ScienceOn
37 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.   DOI
38 Piper, H.M. (1989) Energy deficiency, calcium overload or oxidative stress: possible causes of irreversible ischemic myocardial injury. Klin. Wochenschr., 67, 465-476.   DOI
39 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.   DOI   ScienceOn
40 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.
41 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.   DOI   ScienceOn
42 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   ScienceOn
43 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.   DOI
44 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.   DOI
45 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.   DOI   ScienceOn
46 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.   DOI   ScienceOn
47 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.   DOI   ScienceOn
48 Kim, I. and Lemasters, J.J. (2011) Mitophagy selectively degrades individual damaged mitochondria after photoirradiation. Antioxid. Redox Signaling, 14, 1919-1928.   DOI   ScienceOn
49 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.   DOI   ScienceOn
50 Kim, I., Rodriguez-Enriquez, S. and Lemasters, J.J. (2007) Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys., 462, 245-253.   DOI   ScienceOn
51 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.   DOI   ScienceOn
52 Kim, E.H. and Choi, K.S. (2008) A critical role of superoxide anion in selenite-induced mitophagic cell death. Autophagy, 4, 76-78.   DOI
53 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.   DOI   ScienceOn
54 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.   DOI   ScienceOn
55 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.   DOI   ScienceOn
56 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.   DOI   ScienceOn
57 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.
58 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.   DOI   ScienceOn
59 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.   DOI   ScienceOn
60 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.