Mitophagy and disease: New avenues for pharmacological intervention

Current Pharmaceutical Design

Volumn 17, Issue 20, 2011, Pages 2056-2073

  Taylor, Robert ^a   Goldman, Scott J ^b  

^a UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY   (United States)

^b U S ARMY RESEARCH INSTITUTE OF ENVIRONMENTAL MEDICINE   (United States)

Author keywords

Autophagy; Mitophagy; MMP; MPT; Parkin; PINK1

Indexed keywords

CASPASE INHIBITOR; CHLOROQUINE; ROTENONE; THENOYLTRIFLUOROACETONE;

AGING; ALZHEIMER DISEASE; AUTOPHAGOSOME; AUTOPHAGY; CARDIOVASCULAR DISEASE; CELL DIFFERENTIATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; HUMAN; LIVER DISEASE; MITOCHONDRION; MITOPHAGY; MOLECULAR MECHANICS; NEOPLASM; NERVE DEGENERATION; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PURKINJE CELL; PURKINJE CELL DEGRADATION; RETICULOCYTE; REVIEW; SIGNAL TRANSDUCTION; YEAST;

AUTOPHAGY; CHEMOPREVENTION; HUMANS; MITOCHONDRIA; MOLECULAR TARGETED THERAPY; NEURODEGENERATIVE DISEASES;

EID: 80052256155     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211796904768     Document Type: Review

References (239)

1. Nakagawa I, Amano A, Mizushima N, et al. Autophagy defends cells against invading group A Streptococcus. Science 2004; 306: 1037-40.
2. Paludan C, Schmid D, Landthaler M, et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 2005; 307: 593-6.
3. Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8: 931-7.
4. Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809-20.
5. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100: 15077-82.
6. Tsujimoto Y, Shimizu S. Another way to die: autophagic programmed cell death. Cell Death Differ 2005; 12 Suppl 2: 1528-34.
7. Penka M, Schwarz J, Pavlik T, et al. Essential thrombocytemia and other myeloproliferations with thrombocytemia in the data of the register of patients treated with Thromboreductin till the end of 2006]. Vnitr Lek 2007; 53: 653-61.
8. Kissova I, Salin B, Schaeffer J, et al. Selective and non-selective autophagic degradation of mitochondria in yeast. Autophagy 2007; 3: 329-36.
9. Cuervo AM, Bergamini E, Brunk UT, et al. Autophagy and aging: the importance of maintaining clean cells. Autophagy 2005; 1: 131-40.
10. Rubinsztein DC, DiFiglia M, Heintz N, et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 2005; 1: 11-22.
11. Clark SL, Jr. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope. J Biophys Biochem Cytol 1957; 3: 349-62.
12. Novikoff AB. The proximal tubule cell in experimental hydronephrosis. J Biophys Biochem Cytol 1959; 6: 136-8.
13. Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol 1962; 12: 198-202.
14. Novikoff AB, Essner E. Cytolysomes and mitochondrial degeneration. J Cell Biol 1962; 15: 140-6.
15. De Duve C. General Properties of Lysosomes. In: de Reuck AVS, Cameron MP, ed.^eds., Ciba Foundation Symposium on Lysosomes. Ciba Foundation 1963; pp. 1-35.
16. Matsuura S, Morimoto T, Nagata S, Tashiro Y. Studies on the posterior silk gland of the silkworm, Bombyx mori. II. Cytolytic processes in posterior silk gland cells during metamorphosis from larva to pupa. J Cell Biol 1968; 38: 589-603.
17. Morimoto T, Matsuura S, Nagata S, Tashiro Y. Studies on the posterior silk gland of the silkworm, Bombyx mori. 3. Ultrastructural changes of posterior silk gland cells in the fourth larval instar. J Cell Biol 1968; 38: 604-14.
18. Schafer D. Autophagosomes in cultivated chicken heart cells. Z Zellforsch Mikrosk Anat 1972; 133: 201-10.
19. Latalski M, Halliop J, Obuchowska D. Observations of autophagosomes in the epithelial cells of a rat kidney proximal tubules (author's transl). Ann Univ Mariae Curie Sklodowska Med 1974; 29: 86-91.
20. Ericsson JL. Studies on induced cellular autophagy. II. Characterization of the membranes bordering autophagosomes in parenchymal liver cells. Exp Cell Res 1969; 56: 393-405.
21. Webber MM, Stonington OG. Ultrastructural changes in human prepubertal prostatic epithelium grown in vitro. Invest Urol 1975; 12: 389-400.
22. Lee W. Electron microscopic observations of the rat endometrium during the implantation period, with special reference to its sexsteroid hormone regulation (author's transl). Nippon Naibunpi Gakkai Zasshi 1975; 51: 938-66.
23. Deter RL, Baudhuin P, De Duve C. Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol 1967; 35: C11-6.
24. Pfeifer U. Inhibition by insulin of the physiological autophagic breakdown of cell organelles. Acta Biol Med Ger 1977; 36: 1691-4.
25. Pfeifer U. Inhibition by insulin of the formation of autophagic vacuoles in rat liver. A morphometric approach to the kinetics of intracellular degradation by autophagy. J Cell Biol 1978; 78: 152-67.
26. Mortimore GE, Schworer CM. Induction of autophagy by aminoacid deprivation in perfused rat liver. Nature 1977; 270: 174-6.
27. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 1997; 243: 240-6.
28. Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 1982; 79: 1889-92.
29. Kovacs AL, Molnar K, Seglen PO. Inhibition of autophagic sequestration and endogenous protein degradation in isolated rat hepatocytes by methylated adenosine derivatives. FEBS Lett 1981; 134: 194-6.
30. Kovacs AL, Seglen PO. Inhibition of hepatocytic protein degradation by methylaminopurines and inhibitors of protein synthesis. Biochim Biophys Acta 1981; 676: 213-20.
31. Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 2009; 625: 220-33.
32. Fedorko M. Effect of chloroquine on morphology of cytoplasmic granules in maturing human leukocytes--an ultrastructural study. J Clin Invest 1967; 46: 1932-42.
33. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 1992; 119: 301-11.
34. Klionsky DJ, Cregg JM, Dunn WA, Jr., et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell 2003; 5: 539-45.
35. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 1993; 333: 169-74.
36. Kim J, Klionsky DJ. Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu Rev Biochem 2000; 69: 303-42.
37. Manjithaya R, Nazarko TY, Farre JC, Subramani S. Molecular mechanism and physiological role of pexophagy. FEBS Lett 2010; 584: 1367-73.
38. Sakai Y, Oku M, van der Klei IJ, Kiel JA. Pexophagy: autophagic degradation of peroxisomes. Biochim Biophys Acta 2006; 1763: 1767-75.
39. Dunn WA, Jr., Cregg JM, Kiel JA, et al. Pexophagy: the selective autophagy of peroxisomes. Autophagy 2005; 1: 75-83.
40. Lynch-Day MA, Klionsky DJ. The Cvt pathway as a model for selective autophagy. FEBS Lett 2010; 584: 1359-66.
41. Khalfan WA, Klionsky DJ. Molecular machinery required for autophagy and the cytoplasm to vacuole targeting (Cvt) pathway in S. cerevisiae. Curr Opin Cell Biol 2002; 14: 468-75.
42. Titorenko VI, Keizer I, Harder W, Veenhuis M. Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha. J Bacteriol 1995; 177: 357-63.
43. Harding TM, Morano KA, Scott SV, Klionsky DJ. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol 1995; 131: 591-602.
44. Epple UD, Suriapranata I, Eskelinen EL, Thumm M. Aut5/Cvt17p, a putative lipase essential for disintegration of autophagic bodies inside the vacuole. J Bacteriol 2001; 183: 5942-55.1
45. Mizushima N, Noda T, Ohsumi Y. Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J 1999; 18: 3888-96.
46. Kamada Y, Funakoshi T, Shintani T, et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 2000; 150: 1507-13.
47. Barth H, Meiling-Wesse K, Epple UD, Thumm M. Autophagy and the cytoplasm to vacuole targeting pathway both require Aut10p. FEBS Lett 2001; 508: 23-8.
48. Scott SV, Guan J, Hutchins MU, Kim J, Klionsky DJ. Cvt19 is a receptor for the cytoplasm-to-vacuole targeting pathway. Mol Cell 2001; 7: 1131-41.
49. Nice DC, Sato TK, Stromhaug PE, Emr SD, Klionsky DJ. Cooperative binding of the cytoplasm to vacuole targeting pathway proteins, Cvt13 and Cvt20, to phosphatidylinositol 3-phosphate at the pre-autophagosomal structure is required for selective autophagy. J Biol Chem 2002; 277: 30198-207.
50. Barth H, Meiling-Wesse K, Epple UD, Thumm M. Mai1p is essential for maturation of proaminopeptidase I but not for autophagy. FEBS Lett 2002; 512: 173-9.
51. Suriapranata I, Epple UD, Bernreuther D, et al. The breakdown of autophagic vesicles inside the vacuole depends on Aut4p. J Cell Sci 2000; 113 (Pt 22): 4025-33.
52. Tucker KA, Reggiori F, Dunn WA, Jr., Klionsky DJ. Atg23 is essential for the cytoplasm to vacuole targeting pathway and efficient autophagy but not pexophagy. J Biol Chem 2003; 278: 48445-52.
53. Mukaiyama H, Oku M, Baba M, et al. Paz2 and 13 other PAZ gene products regulate vacuolar engulfment of peroxisomes during micropexophagy. Genes Cells 2002; 7: 75-90.
54. Wurmser AE, Emr SD. Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy. J Cell Biol 2002; 158: 761-72.
55. Matsuura A, Tsukada M, Wada Y, Ohsumi Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 1997; 192: 245-50.
56. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22: 124-31.
57. Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007; 9: 1102-9.
58. Yang Z, Klionsky DJ. An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 2009; 335: 1-32.
59. Inoue Y, Klionsky DJ. Regulation of macroautophagy in Saccharomyces cerevisiae. Semin Cell Dev Biol; 21: 664-70.
60. Kamada Y, Yoshino K, Kondo C, et al. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol 2010; 30: 1049-58.
61. Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 2008; 90: 313-23.
62. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 2010; 40: 310-22.
63. Tooze SA, Yoshimori T. The origin of the autophagosomal membrane. Nat Cell Biol 2010; 12: 831-5.
64. Xie Z, Nair U, Klionsky DJ. Dissecting autophagosome formation: the missing pieces. Autophagy 2008; 4: 920-2.
65. Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4: 151-75.
66. Huang WP, Scott SV, Kim J, Klionsky DJ. The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem 2000; 275: 5845-51.
67. Noda T, Kim J, Huang WP, et al. Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. J Cell Biol 2000; 148: 465-80.
68. He C, Song H, Yorimitsu T, et al. Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast. J Cell Biol 2006; 175: 925-35.
69. Kim J, Kamada Y, Stromhaug PE, et al. Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole. J Cell Biol 2001; 153: 381-96.
70. Shintani T, Huang WP, Stromhaug PE, Klionsky DJ. Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. Dev Cell 2002; 3: 825-37.
71. Randow F. How cells deploy ubiquitin and autophagy to defend their cytosol from bacterial invasion. Autophagy 2011; 7.
72. Xu Y, Eissa NT. Autophagy in innate and adaptive immunity. Proc Am Thorac Soc 2010; 7: 22-8.
73. Galluzzi L, Kepp O, Zitvogel L, Kroemer G. Bacterial invasion: linking autophagy and innate immunity. Curr Biol 2010; 20: R106-8.
74. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12: 814-22.
75. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005; 102: 8204-9.
76. Crighton D, Wilkinson S, O'Prey J, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006; 126: 121-34.
77. Gordon PB, Seglen PO. Autophagic sequestration of [14C]sucrose, introduced into rat hepatocytes by reversible electropermeabilization. Exp Cell Res 1982; 142: 1-14.
78. Seglen PO, Gordon PB, Tolleshaug H, Hoyvik H. Use of [3H]raffinose as a specific probe of autophagic sequestration. Exp Cell Res 1986; 162: 273-7.
79. Gordon PB, Seglen PO. Prelysosomal convergence of autophagic and endocytic pathways. Biochem Biophys Res Commun 1988; 151: 40-7.
80. Bjorkoy G, Lamark T, Brech A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 2005; 171: 603-14.
81. Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007; 282: 24131-45.
82. Wang QJ, Ding Y, Kohtz DS, et al. Induction of autophagy in axonal dystrophy and degeneration. J Neurosci 2006; 26: 8057-68.
83. Komatsu M, Wang QJ, Holstein GR, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci USA 2007; 104: 14489-94.
84. Bjorkoy G, Lamark T, Pankiv S, et al. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol 2009; 452: 181-97.
85. Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000; 19: 5720-8.
86. Mizushima N. Methods for monitoring autophagy using GFP-LC3 transgenic mice. Methods Enzymol 2009; 452: 13-23.
87. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004; 15: 1101-11.
88. Melendez A, Talloczy Z, Seaman M, et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003; 301: 1387-91.
89. Otto GP, Wu MY, Kazgan N, Anderson OR, Kessin RH. Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum. J Biol Chem 2003; 278: 17636-45.
90. Rusten TE, Lindmo K, Juhasz G, et al. Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev Cell 2004; 7: 179-92.
91. Scott RC, Schuldiner O, Neufeld TP. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 2004; 7: 167-78.
92. Cheong H, Klionsky DJ. Biochemical methods to monitor autophagy-related processes in yeast. Methods Enzymol 2008; 451: 1-26.
93. Zhang J, Wu XJ, Zhuo DX, et al. Effect of tankyrase 1 on autophagy in the corpus cavernosum smooth muscle cells from ageing rats with erectile dysfunction and its potential mechanism. Asian J Androl 2010; 12: 744-52.
94. He C, Klionsky DJ. Analyzing autophagy in zebrafish. Autophagy 2010; 6.
95. Noda T, Klionsky DJ. The quantitative Pho8Delta60 assay of nonspecific autophagy. Methods Enzymol 2008; 451: 33-42.
96. Campbell CL, Thorsness PE. Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments. J Cell Sci 1998; 111 (Pt 16): 2455-64.
97. Jezek P, Hlavata L. Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol 2005; 37: 2478-503.
98. Wojcik M, Burzynska-Pedziwiatr I, Wozniak LA. A review of natural and synthetic antioxidants important for health and longevity. Curr Med Chem 2010; 17: 3262-88.
99. Knight JA. The biochemistry of aging. Adv Clin Chem 2000; 35: 1-62.
100. Chen H, Chan DC. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 2009; 18: R169-76.
101. Jendrach M, Mai S, Pohl S, Voth M, Bereiter-Hahn J. Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress. Mitochondrion 2008; 8: 293-304.
102. Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 2005; 8: 3-5.
103. Kissova I, Deffieu M, Manon S, Camougrand N. Uth1p is involved in the autophagic degradation of mitochondria. J Biol Chem 2004; 279: 39068-74.
104. Tal R, Winter G, Ecker N, Klionsky DJ, Abeliovich H. Aup1p, a yeast mitochondrial protein phosphatase homolog, is required for efficient stationary phase mitophagy and cell survival. J Biol Chem 2007; 282: 5617-24.
105. Nowikovsky K, Reipert S, Devenish RJ, Schweyen RJ. Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy. Cell Death Differ 2007; 14: 1647-56.
106. Priault M, Salin B, Schaeffer J, et al. Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ 2005; 12: 1613-21.
107. Zhang Y, Qi H, Taylor R, et al. The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy 2007; 3: 337-46.
108. Kanki T, Kang D, Klionsky DJ. Monitoring mitophagy in yeast: the Om45-GFP processing assay. Autophagy 2009; 5: 1186-9.
109. Kanki T, Wang K, Baba M, et al. A genomic screen for yeast mutants defective in selective mitochondria autophagy. Mol Biol Cell 2009; 20: 4730-8.
110. Okamoto K, Kondo-Okamoto N, Ohsumi Y. A landmark protein essential for mitophagy: Atg32 recruits the autophagic machinery to mitochondria. Autophagy 2009; 5: 1203-5.
111. Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell 2009; 17: 98-109.
112. Lemasters JJ, Qian T, Elmore SP, et al. Confocal microscopy of the mitochondrial permeability transition in necrotic cell killing, apoptosis and autophagy. Biofactors 1998; 8: 283-5.
113. Rodriguez-Enriquez S, Kim I, Currin RT, Lemasters JJ. Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2006; 2: 39-46.
114. Elmore SP, Qian T, Grissom SF, Lemasters JJ. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 2001; 15: 2286-7.
115. Kim I, Lemasters JJ. Mitophagy Selectively Degrades Individual Damaged Mitochondria After Photoirradiation. Antioxid Redox Signal 2010.
116. Berman SB, Pineda FJ, Hardwick JM. Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ 2008; 15: 1147-52.
117. Parone PA, Da Cruz S, Tondera D, et al. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS One 2008; 3: e3257.
118. Arnoult D, Rismanchi N, Grodet A, et al. Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 2005; 15: 2112-8.
119. Twig G, Elorza A, Molina AJ, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27: 433-46.
120. Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 2008; 1777: 1092-7.
121. Kundu M, Lindsten T, Yang CY, et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 2008; 112: 1493-502.
122. Mortensen M, Ferguson DJ, Edelmann M, et al. Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc Natl Acad Sci USA 2010; 107: 832-7.
123. Zhang J, Randall MS, Loyd MR, et al. Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation. Blood 2009; 114: 157-64.
124. Zhang J, Ney PA. Autophagy-dependent and -independent mechanisms of mitochondrial clearance during reticulocyte maturation. Autophagy 2009; 5: 1064-5.
125. Schweers RL, Zhang J, Randall MS, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci USA 2007; 104: 19500-5.
126. Schwarten M, Mohrluder J, Ma P, et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy 2009; 5: 690-8.
127. Novak I, Kirkin V, McEwan DG, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 2010; 11: 45-51.
128. Sandoval H, Thiagarajan P, Dasgupta SK, et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 2008; 454: 232-5.
129. Chen M, Sandoval H, Wang J. Selective mitochondrial autophagy during erythroid maturation. Autophagy 2008; 4: 926-8.
130. Zhang J, Ney PA. NIX induces mitochondrial autophagy in reticulocytes. Autophagy 2008; 4: 354-6.
131. Ding WX, Ni HM, Li M, et al. 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 2010; 285: 27879-90.
132. Hatano Y, Li Y, Sato K, et al. Novel PINK1 mutations in earlyonset parkinsonism. Ann Neurol 2004; 56: 424-7.
133. Rohe CF, Montagna P, Breedveld G, et al. Homozygous PINK1 Cterminus mutation causing early-onset parkinsonism. Ann Neurol 2004; 56: 427-31.
134. Deng H, Dodson MW, Huang H, Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci USA 2008; 105: 14503-8.
135. Poole AC, Thomas RE, Andrews LA, et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 2008; 105: 1638-43.
136. Yang Y, Ouyang Y, Yang L, et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA 2008; 105: 7070-5.
137. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183: 795-803.
138. Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010; 8: e1000298.
139. Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010; 189: 211-21.
140. Kim Y, Park J, Kim S, et al. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 2008; 377: 975-80.
141. Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP. Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol 2010; 189: 671-9.
142. Ziviani E, Tao RN, Whitworth AJ. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 2010; 107: 5018-23.
143. Gegg ME, Cooper JM, Chau KY, et al. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 2010; 19: 4861-70.
144. Okatsu K, Saisho K, Shimanuki M, et al. P62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 2010; 15: 887-900.
145. Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 2010; 6: 1090-106.
146. Livnat-Levanon N, Glickman MH. Ubiquitin-Proteasome System and mitochondria - Reciprocity. Biochim Biophys Acta; 1809: 80-7.
147. Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One; 5: e10054.
148. Geisler S, Holmstrom KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol; 12: 119-31.
149. Ziviani E, Whitworth AJ. How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 2010; 6.
150. Gegg ME, Schapira AH. PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis. Autophagy 2011; 7: 243-5.
151. Chan NC, Salazar AM, Pham AH, et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 2011.
152. Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002; 11: 1107-17.
153. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278: 25009-13.
154. Yu WH, Cuervo AM, Kumar A, et al. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 2005; 171: 87-98.
155. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880-4.
156. Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006; 441: 885-9.
157. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010; 362: 329-44.
158. Smith MA. Alzheimer disease. Int Rev Neurobiol 1998; 42: 1-54.
159. Moreira PI, Duarte AI, Santos MS, Rego AC, Oliveira CR. An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer's disease. J Alzheimers Dis 2009; 16: 741-61.
160. Resende R, Moreira PI, Proenca T, et al. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 2008; 44: 2051-7.
161. Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60: 759-67.
162. Wallace DC, Stugard C, Murdock D, Schurr T, Brown MD. Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations. Proc Natl Acad Sci USA 1997; 94: 14900-5.
163. Coskun PE, Beal MF, Wallace DC. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 2004; 101: 10726-31.
164. Moreira PI, Santos MS, Moreno AM, Seica R, Oliveira CR. Increased vulnerability of brain mitochondria in diabetic (Goto- Kakizaki) rats with aging and amyloid-beta exposure. Diabetes 2003; 52: 1449-56.
165. Moreira PI, Santos MS, Moreno A, Oliveira C. Amyloid betapeptide promotes permeability transition pore in brain mitochondria. Biosci Rep 2001; 21: 789-800.
166. Moreira PI, Santos MS, Moreno A, Rego AC, Oliveira C. Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 2002; 69: 257-67.
167. Ribe EM, Serrano-Saiz E, Akpan N, Troy CM. Mechanisms of neuronal death in disease: defining the models and the players. Biochem J 2008; 415: 165-82.
168. Wang X, Su B, Fujioka H, Zhu X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. Am J Pathol 2008; 173: 470-82.
169. Wang X, Su B, Siedlak SL, et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008; 105: 19318-23.
170. Wang X, Su B, Zheng L, et al. The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J Neurochem 2009; 109 Suppl 1: 153-9.
171. Nakada K, Inoue K, Ono T, et al. Inter-mitochondrial complementation: Mitochondria-specific system preventing micefrom expression of disease phenotypes by mutant mtDNA. Nat Med 2001; 7: 934-40.
172. Hald A, Lotharius J. Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 2005; 193: 279-90.
173. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000; 3: 1301-6.
174. Burbulla LF, Krebiehl G, Kruger R. Balance is the challenge--the impact of mitochondrial dynamics in Parkinson's disease. Eur J Clin Invest 2010; 40: 1048-60.
175. Bueler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol 2009; 218: 235-46.
176. Mitsui T, Kuroda Y, Kaji R. Parkin and mitochondria. Brain Nerve 2008; 60: 923-9.
177. Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006; 441: 1157-61.
178. Yang Y, Gehrke S, Imai Y, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci USA 2006; 103: 10793-8.
179. Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006; 441: 1162-6.
180. Springer W, Kahle PJ. Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 2011; 7.
181. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol 2008; 7: 97-109.
182. Mullen RJ, Eicher EM, Sidman RL. Purkinje cell degeneration, a new neurological mutation in the mouse. Proc Natl Acad Sci USA 1976; 73: 208-12.
183. Chakrabarti L, Eng J, Ivanov N, Garden GA, La Spada AR. Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death. Mol Brain 2009; 2: 24.
184. Cuervo AM. Autophagy and aging: keeping that old broom working. Trends Genet 2008; 24: 604-12.
185. Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672-6.
186. Chen N, Karantza-Wadsworth V. Role and regulation of autophagy in cancer. Biochim Biophys Acta 2009; 1793: 1516-23.
187. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 298-300.
188. Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972; 20: 145-7.
189. Lee HC, Chang CM, Chi CW. Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 2010; 9 Suppl 1: S47-58.
190. Edgar D, Trifunovic A. The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging. Aging (Albany NY) 2009; 1: 1028-32.
191. Kujoth GC, Hiona A, Pugh TD, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005; 309: 481-4.
192. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998; 97: 282-9.
193. Doenst T, Pytel G, Schrepper A, et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res 2010; 86: 461-70.
194. Marin-Garcia J, Goldenthal MJ, Damle S, Pi Y, Moe GW. Regional distribution of mitochondrial dysfunction and apoptotic remodeling in pacing-induced heart failure. J Card Fail 2009; 15: 700-8.
195. Murray AJ, Cole MA, Lygate CA, et al. Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart. J Mol Cell Cardiol 2008; 44: 694-700.
196. Baines CP. The cardiac mitochondrion: nexus of stress. Annu Rev Physiol 2010; 72: 61-80.
197. Gustafsson AB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovasc Res 2008; 77: 334-43.
198. Jung C, Martins AS, Niggli E, Shirokova N. Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways. Cardiovasc Res 2008; 77: 766-73.
199. Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 2008; 102: 488-96.
200. Ausma J, Thone F, Dispersyn GD, et al. Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant. Mol Cell Biochem 1998; 186: 159-68.
201. Hom J, Sheu SS. Morphological dynamics of mitochondria--a special emphasis on cardiac muscle cells. J Mol Cell Cardiol 2009; 46: 811-20.
202. Jones M, Ferrans VJ, Morrow AG, Roberts WC. Ultrastructure of crista supraventricularis muscle in patients with congenital heart diseases associated with right ventricular outflow tract obstruction. Circulation 1975; 51: 39-67.
203. Schaper J, Froede R, Hein S, et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 1991; 83: 504-14.
204. Chen L, Gong Q, Stice JP, Knowlton AA. Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 2009; 84: 91-9.
205. Bugger H, Schwarzer M, Chen D, et al. Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc Res 2010; 85: 376-84.
206. Hom J, Yu T, Yoon Y, Porter G, Sheu SS. Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes. Biochim Biophys Acta 2010; 1797: 913-21.
207. Parra V, Eisner V, Chiong M, et al. Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res 2008; 77: 387-97.
208. Gottlieb RA, Mentzer RM. Autophagy during cardiac stress: joys and frustrations of autophagy. Annu Rev Physiol 2010; 72: 45-59.
209. Nakai A, Yamaguchi O, Takeda T, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 2007; 13: 619-24.
210. Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 2000; 406: 906-10.
211. Tanaka Y, Guhde G, Suter A, et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 2000; 406: 902-6.
212. Sohal DS, Nghiem M, Crackower MA, et al. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ Res 2001; 89: 20-5.
213. Zhu H, Tannous P, Johnstone JL, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 2007; 117: 1782-93.
214. Komatsu M, Waguri S, Ueno T, et al. Impairment of starvationinduced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005; 169: 425-34.
215. Zhang Y, Goldman S, Baerga R, et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci USA 2009; 106: 19860-5.
216. Singh R, Xiang Y, Wang Y, et al. Autophagy regulates adipose mass and differentiation in mice. J Clin Invest 2009; 119: 3329-39.
217. Rautou PE, Mansouri A, Lebrec D, et al. Autophagy in liver diseases. J Hepatol 2010; 53: 1123-34.
218. Donohue TM, Jr. Autophagy and ethanol-induced liver injury. World J Gastroenterol 2009; 15: 1178-85.
219. Kim JS, Nitta T, Mohuczy D, et al. Impaired autophagy: A mechanism of mitochondrial dysfunction in anoxic rat hepatocytes. Hepatology 2008; 47: 1725-36.
220. Takamura A, Komatsu M, Hara T, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 2011; 25: 795-800.
221. Poso AR, Hirsimaki P. Inhibition of proteolysis in the liver by chronic ethanol feeding. Biochem J 1991; 273(Pt 1): 149-52.
222. Baraona E, Leo MA, Borowsky SA, Lieber CS. Alcoholic hepatomegaly: accumulation of protein in the liver. Science 1975; 190: 794-5.
223. Harada M. Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes. Med Mol Morphol 2010; 43: 13-8.
224. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nat Cell Biol 2010; 12: 842-6.
225. Koubova J, Guarente L. How does calorie restriction work? Genes Dev 2003; 17: 313-21.
226. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA 2004; 101: 6659-63.
227. Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 2011; 7: 9-17.
228. Madeo F, Eisenberg T, Buttner S, Ruckenstuhl C, Kroemer G. Spermidine: a novel autophagy inducer and longevity elixir. Autophagy 2010; 6: 160-2.
229. Hayakawa Y, Chandra M, Miao W, et al. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 2003; 108: 3036-41.
230. Holly TA, Drincic A, Byun Y, et al. Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo. J Mol Cell Cardiol 1999; 31: 1709-15.
231. Chua CC, Gao J, Ho YS, et al. Overexpression of IAP-2 attenuates apoptosis and protects against myocardial ischemia/reperfusion injury in transgenic mice. Biochim Biophys Acta 2007; 1773: 577-83.
232. Chen Z, Chua CC, Ho YS, Hamdy RC, Chua BH. Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 2001; 280: H2313-20.
233. Camins A, Verdaguer E, Junyent F, et al. Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium. CNS Neurosci Ther 2009; 15: 333-44.
234. Schumacker PT. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 2006; 10: 175-6.
235. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009; 8: 579-91.
236. Pelicano H, Feng L, Zhou Y, et al. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 2003; 278: 37832-9.
237. Scherz-Shouval R, Shvets E, Fass E, et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2007; 26: 1749-60.
238. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J Cell Sci 2007; 120: 4155-66.
239. Gargini R, Garcia-Escudero V, Izquierdo M. Therapy mediated by mitophagy abrogates tumor progression. Autophagy 2011; 7.