Mechanisms of mitochondria and autophagy crosstalk

Cell Cycle

Volumn 10, Issue 23, 2011, Pages 4032-4038

  Rambold, Angelika S ^a   Lippincott Schwartz, Jennifer ^a  

^a EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

Author keywords

Apoptosis; Autophagy; Fission; Fusion; Mitochondria

Indexed keywords

PROTEIN BCL 2;

APOPTOSIS; AUTOPHAGY; CELL SURVIVAL; DEGRADATION KINETICS; HUMAN; MITOCHONDRION; NUTRIENT; PARKINSON DISEASE; PROTEIN BINDING; PROTEIN LOCALIZATION; PROTEIN SECRETION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

EID: 82855181509     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.10.23.18384     Document Type: Review

References (123)

1. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 2009; 10:458- 67; PMID:19491929; DOI:10.1038/nrm2708.
2. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22:124-31; PMID:20034776; DOI:10.1016/j.ceb.2009.11.014.
3. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451:1069-75; PMID:18305538; DOI:10.1038/nature06639.
4. 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; PMID:19029340; DOI:10.1083/jcb.200809125.
5. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, et al. PINK1/Parkinmediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12:119-31; PMID:20098416; DOI:10.1038/ncb2012.
6. Geisler S, Holmstrom KM, Treis A, Skujat D, Weber SS, Fiesel FC, et al. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 2010; 6:871-8; PMID:20798600; DOI:10.4161/auto.6.7.13286.
7. Graef M, Nunnari J. Mitochondria regulate autophagy by conserved signalling pathways. EMBO J 2011; 30:2101-14; PMID:21468027; DOI:10.1038/ emboj.2011.104.
8. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 2010; 141:656-67; PMID:20478256; DOI:10.1016/j.cell.2010.04. 009.
9. Las G, Sereda S, Wikstrom JD, Twig G, Shirihai OS. Fatty acids suppress autophagic turnover in {beta}-cells. J Biol Chem; PMID:21859708.
10. Hoppins S, Nunnari J. The molecular mechanism of mitochondrial fusion. Biochim Biophys Acta 2009; 1793:20-6; PMID:18691613; DOI:10.1016/j.bbamcr. 2008.07.005.
11. Lackner LL, Nunnari JM. The molecular mechanism and cellular functions of mitochondrial division. Biochim Biophys Acta 2009; 1792:1138-44; PMID:19100831.
12. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 2010; 191:1141- 58; PMID:21149567; DOI:10.1083/jcb.201007152.
13. Mitra K, Wunder C, Roysam B, Lin G, Lippincott- Schwartz J. A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci USA 2009; 106:11960-5; PMID:19617534; DOI:10.1073/pnas.0904875106.
14. Soubannier V, McBride HM. Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 2009; 1793:154-70; PMID:18694785; DOI:10.1016/j.bbamcr.2008.07.008.
15. Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S. MARCH-V is a novel mitofusin 2- and Drp1- binding protein able to change mitochondrial morphology. EMBO Rep 2006; 7:1019-22; PMID:16936636; DOI:10.1038/sj.embor.7400790.
16. Park YY, Lee S, Karbowski M, Neutzner A, Youle RJ, Cho H. Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1. J Cell Sci 2010; 123:619-26; PMID:20103533; DOI:10.1242/ jcs.061481.
17. Duvezin-Caubet S, Jagasia R, Wagener J, Hofmann S, Trifunovic A, Hansson A, et al. Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 2006; 281:37972-9; PMID:17003040; DOI:10.1074/jbc. M606059200.
18. Griparic L, Kanazawa T, van der Bliek AM. Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 2007; 178:757-64; PMID:17709430; DOI:10.1083/jcb.200704112.
19. Ishihara N, Fujita Y, Oka T, Mihara K. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 2006; 25:2966-77; PMID:16778770; DOI:10.1038/sj.emboj.7601184.
20. Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential and Yme1L. J Cell Biol 2007; 178:749-55; PMID:17709429; DOI:10.1083/jcb.200704110.
21. Busch KB, Bereiter-Hahn J, Wittig I, Schagger H, Jendrach M. Mitochondrial dynamics generate equal distribution but patchwork localization of respiratory Complex I. Mol Membr Biol 2006; 23:509-20; PMID:17127623; DOI:10.1080/09687860600877292.
22. Jakobs S. High resolution imaging of live mitochondria. Biochim Biophys Acta 2006; 1763:561-75; PMID:16750866; DOI:10.1016/j.bbamcr. 2006.04.004.
23. Jakobs S, Schauss AC, Hell SW. Photoconversion of matrix targeted GFP enables analysis of continuity and intermixing of the mitochondrial lumen. FEBS Lett 2003; 554:194-200; PMID:14596939; DOI:10.1016/ S0014-5793(03)01170-0.
24. Karbowski M, Arnoult D, Chen H, Chan DC, Smith CL, Youle RJ. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol 2004; 164:493-9; PMID:14769861; DOI:10.1083/jcb.200309082.
25. Nakada K, Inoue K, Ono T, Isobe K, Ogura A, Goto YI, et al. Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 2001; 7:934-40; PMID:11479626; DOI:10.1038/90976.
26. Ono T, Isobe K, Nakada K, Hayashi JI. Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet 2001; 28:272-5; PMID:11431699; DOI:10.1038/90116.
27. Twig G, Graf SA, Wikstrom JD, Mohamed H, Haigh SE, Elorza A, et al. Tagging and tracking individual networks within a complex mitochondrial web with photoactivatable GFP. Am J Physiol Cell Physiol 2006; 291:176-84; PMID:16481372; DOI:10.1152/ ajpcell.00348.2005.
28. Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Graber S, et al. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 2006; 25:3900-11; PMID:16874299; DOI:10.1038/sj. emboj.7601253.
29. Gomes LC, Scorrano L. High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochim Biophys Acta 2008; 1777:860-6; PMID:18515060; DOI:10.1016/j.bbabio.2008.05.442.
30. Malena A, Loro E, Di Re M, Holt IJ, Vergani L. Inhibition of mitochondrial fission favours mutant over wild-type mitochondrial DNA. Hum Mol Genet 2009; 18:3407-16; PMID:19561330; DOI:10.1093/hmg/ ddp281.
31. Suen DF, Narendra DP, Tanaka A, Manfredi G, Youle RJ. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc Natl Acad Sci USA 2010; 107:11835-40; PMID:20547844; DOI:10.1073/pnas.0914569107.
32. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27:433-46; PMID:18200046; DOI:10.1038/sj.emboj.7601963.
33. Amchenkova AA, Bakeeva LE, Chentsov YS, Skulachev VP, Zorov DB. Coupling membranes as energytransmitting cables. I. Filamentous mitochondria in fibroblasts and mitochondrial clusters in cardiomyocytes. J Cell Biol 1988; 107:481-95; PMID:3417757; DOI:10.1083/jcb.107.2.481.
34. Aon MA, Cortassa S, O'Rourke B. Percolation and criticality in a mitochondrial network. Proc Natl Acad Sci USA 2004; 101:4447-52; PMID:15070738; DOI:10.1073/pnas.0307156101.
35. Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N. Ca(2+) homeostasis during mitochondrial fragmentation and perinuclear clustering induced by hFis1. J Biol Chem 2004; 279:22704-14; PMID:15024001; DOI:10.1074/jbc. M312366200.
36. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1 and Opa1 in apoptosis. Mol Biol Cell 2004; 15:5001-11; PMID:15356267; DOI:10.1091/mbc.E04-04-0294.
37. Skulachev VP. Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem Sci 2001; 26:23-9; PMID:11165513; DOI:10.1016/S0968-0004(00)01735-7.
38. Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M, et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 2008; 454:232-5; PMID:18454133; DOI:10.1038/ nature07006.
39. Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci USA 2007; 104:19500-5; PMID:18048346; DOI:10.1073/pnas. 0708818104.
40. Sato M, Sato K. Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos. Science 2011; DOI: 10.1126/science.1210333
41. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87:99-163; PMID:17237344; DOI:10.1152/physrev. 00013.2006.
42. Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 2010; 191:933-42; PMID:21115803; DOI:10.1083/jcb.201008084.
43. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, 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; PMID:20404107; DOI:10.1083/jcb.200910140.
44. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010;8:1000298; PMID:20126261; DOI:10.1371/ journal.pbio.1000298.
45. Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 2008;105:20567-74; PMID:19074260; DOI:10.1073/pnas.0810611105.
46. Sha D, Chin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NFkappaB signaling. Hum Mol Genet 2010; 19:352-63; PMID:19880420; DOI:10.1093/hmg/ddp501.
47. Shiba K, Arai T, Sato S, Kubo S, Ohba Y, Mizuno Y, et al. Parkin stabilizes PINK1 through direct interaction. Biochem Biophys Res Commun 2009; 383:331-5; PMID:19358826; DOI:10.1016/j.bbrc.2009.04.006.
48. Um JW, Stichel-Gunkel C, Lubbert H, Lee G, Chung KC. Molecular interaction between parkin and PINK1 in mammalian neuronal cells. Mol Cell Neurosci 2009; 40:421-32; PMID:19167501; DOI:10.1016/j. mcn.2008.12.010.
49. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 2010; 107:378-83; PMID:19966284; DOI:10.1073/ pnas.0911187107.
50. Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL, et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 2011; 20:1726-37; PMID:21296869; DOI:10.1093/hmg/ ddr048.
51. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 2010; 19:4861-70; PMID:20871098; DOI:10.1093/hmg/ ddq419.
52. 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; PMID:20457763; DOI:10.1083/jcb. 201001039.
53. Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 2010; 191:1367-80; PMID:21173115; DOI:10.1083/jcb.201007013.
54. 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; PMID:20194754; DOI:10.1073/pnas.0913485107.
55. Ziviani E, Whitworth AJ. How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 2010; 6; PMID:20484985; DOI:10.4161/ auto.6.5.12242.
56. Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 2010; 15:887-900; PMID:20604804.
57. Mortensen M, Ferguson DJ, Simon AK. Mitochondrial clearance by autophagy in developing erythrocytes: clearly important, but just how much so? Cell Cycle 2010; 9:1901-6; PMID:20495377; DOI:10.4161/cc.9.10.11603.
58. Ding WX, Ni HM, Li M, Liao Y, Chen X, Stolz DB, 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; PMID:20573959; DOI:10.1074/jbc.M110.119537.
59. Ebato C, Uchida T, Arakawa M, Komatsu M, Ueno T, Komiya K, et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab 2008; 8:325-32; PMID:18840363; DOI:10.1016/j. cmet.2008.08.009.
60. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is required to maintain muscle mass. Cell Metab 2009; 10:507-15; PMID:19945408; DOI:10.1016/j.cmet.2009.10.008.
61. Mortensen M, Ferguson DJ, Edelmann M, Kessler B, Morten KJ, Komatsu 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; PMID:20080761; DOI:10.1073/ pnas.0913170107.
62. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 2007; 13:619-24; PMID:17450150; DOI:10.1038/nm1574.
63. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 2007; 204:25-31; PMID:17190837; DOI:10.1084/jem.20061303.
64. Stephenson LM, Miller BC, Ng A, Eisenberg J, Zhao Z, Cadwell K, et al. Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes. Autophagy 2009; 5:625-35; PMID:19276668; DOI:10.4161/auto.5.5.8133.
65. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010; 6; PMID:20431347; DOI:10.4161/auto.6.5.11947.
66. Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 2011; 13:589-98; PMID:21478857; DOI:10.1038/ncb2220.
67. Rambold AS, Kostelecky B, Elia N, Lippincott- Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 2011; 108:10190-5; PMID:21646527; DOI:10.1073/ pnas.1107402108.
68. Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H, et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 2006; 15:883-95; PMID:16449237; DOI:10.1093/hmg/ ddl006.
69. Lutz AK, Exner N, Fett ME, Schlehe JS, Kloos K, Lammermann K, et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 2009; 284:22938-51; PMID:19546216; DOI:10.1074/jbc.M109.035774.
70. Radoshevich L, Murrow L, Chen N, Fernandez E, Roy S, Fung C, et al. ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell 2010; 142:590-600; PMID:20723759; DOI:10.1016/j.cell.2010.07.018.
71. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol- 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 2008; 182:685- 701; PMID:18725538; DOI:10.1083/jcb. 200803137.
72. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 2010; 12:747-57; PMID:20639872; DOI:10.1038/ncb2078.
73. Young AR, Chan EY, Hu XW, Kochl R, Crawshaw SG, High S, et al. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 2006; 119:3888-900; PMID:16940348; DOI:10.1242/jcs.03172.
74. Rambold AS, Lippincott-Schwartz J. Starved cells use mitochondria for autophagosome biogenesis. Cell Cycle 2010; 9:3633-4; PMID:20855967; DOI:10.4161/cc.9.18.13170.
75. Furuya N, Yu J, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 2005; 1:46-52; PMID:16874027; DOI:10.4161/auto.1.1.1542.
76. Kihara A, Noda T, Ishihara N, Ohsumi Y. Two distinct Vps34 phosphatidylinositol-3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 2001; 152:519-30; PMID:11157979; DOI:10.1083/jcb.152.3.519.
77. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402:672-6; PMID:10604474; DOI:10.1038/45257.
78. Tassa A, Roux MP, Attaix D, Bechet DM. Class III phosphoinositide-3- kinase-Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J 2003; 376:577-86; PMID:12967324; DOI:10.1042/BJ20030826.
79. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122:927-39; PMID:16179260; DOI:10.1016/j. cell.2005.07.002.
80. Strappazzon F, Vietri-Rudan M, Campello S, Nazio F, Florenzano F, Fimia GM, et al. Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. EMBO J 2011; 30:1195-208; PMID:21358617; DOI:10.1038/ emboj.2011.49.
81. Pierrat B, Simonen M, Cueto M, Mestan J, Ferrigno P, Heim J. SH3GLB, a new endophilin-related protein family featuring an SH3 domain. Genomics 2001; 71:222-34; PMID:11161816; DOI:10.1006/ geno.2000.6378.
82. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9:1142-51; PMID:17891140; DOI:10.1038/ncb1634.
83. Takahashi Y, Meyerkord CL, Wang HG. BARgaining membranes for autophagosome formation: Regulation of autophagy and tumorigenesis by Bif-1/Endophilin B1. Autophagy 2008; 4:121-4; PMID:18032918.
84. Takahashi Y, Meyerkord CL, Wang HG. Bif-1/ endophilin B1: a candidate for crescent driving force in autophagy. Cell Death Differ 2009; 16:947-55; PMID:19265852; DOI:10.1038/cdd.2009.19.
85. Karbowski M, Jeong SY, Youle RJ. Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol 2004; 166:1027-39; PMID:15452144; DOI:10.1083/jcb.200407046.
86. Vance JE. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 2008; 49:1377- 87; PMID:18204094; DOI:10.1194/jlr.R700020- JLR200.
87. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature 2004; 432:1032-6; PMID:15525940; DOI:10.1038/ nature03029.
88. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011; 17:654-66; PMID:21325294; DOI:10.1158/1078- 0432.CCR-10-2634.
89. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation and tumorigenesis. Cancer Cell 2006; 10:51-64; PMID:16843265; DOI:10.1016/j.ccr. 2006.06.001.
90. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137:1062-75; PMID:19524509; DOI:10.1016/j.cell.2009.03.048.
91. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007; 21:1367-81; PMID:17510285; DOI:10.1101/gad.1545107.
92. Wu JJ, Quijano C, Chen E, Liu H, Cao L, Fergusson MM, et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Albany NY) 2009; 1:425-37; PMID:20157526.
93. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 2008; 456:259-63; PMID:18849966; DOI:10.1038/nature07416.
94. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006; 441:885-9; PMID:16625204; DOI:10.1038/nature04724.
95. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, et al. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany NY) 2009; 1:961-70; PMID:20157579.
96. Raimundo N, Shadel GSA. "radical" mitochondrial view of autophagy-related pathology. Aging (Albany NY) 2009; 1:354-6; PMID:20157522.
97. Egan D, Kim J, Shaw RJ, Guan KL. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 2011; 7:643-4; PMID:21460621; DOI:10.4161/ auto.7.6.15123.
98. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011; 331:456- 61; PMID:21205641; DOI:10.1126/science.1196371.
99. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30:214-26; PMID:18439900; DOI:10.1016/j.molcel.2008.03.003.
100. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115:577-90; PMID:14651849; DOI:10.1016/S0092-8674(03)00929-2.
101. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132-41; PMID:21258367; DOI:10.1038/ncb2152.
102. Lee JW, Park S, Takahashi Y, Wang HG. The association of AMPK with ULK1 regulates autophagy. PLoS ONE 2010; 5:15394; PMID:21072212; DOI:10.1371/journal. pone.0015394.
103. Löffler AS, Alers S, Dieterle AM, Keppeler H, Franz- Wachtel M, Kundu M, et al. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 2010; 7:696-706; PMID:21460634; DOI:10.4161/auto.7.7.15451.
104. Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci USA 2011; 108:4788-93; PMID:21383122; DOI:10.1073/pnas.1100844108.
105. Hardie DG. Sensing of energy and nutrients by AMPactivated protein kinase. Am J Clin Nutr 2011; 93:891- 6; PMID:21325438; DOI:10.3945/ajcn.110. 001925.
106. Hardie DG. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem Soc Trans 2011; 39:1-13; PMID:21265739; DOI:10.1042/BST0390001.
107. Desai BN, Myers BR, Schreiber SL. FKBP12- rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci USA 2002; 99:4319- 24; PMID:11930000; DOI:10.1073/pnas.261702698.
108. Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006; 281:27643-52; PMID:16847060; DOI:10.1074/jbc.M603536200.
109. Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010; 466:68-76; PMID:20562859; DOI:10.1038/ nature09204.
110. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007; 450:736-40; PMID:18046414; DOI:10.1038/nature06322.
111. Ramanathan A, Schreiber SL. Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA 2009; 106:22229-32; PMID:20080789; DOI:10.1073/pnas.0912074106.
112. Reznick RM, Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol 2006; 574:33-9; PMID:16709637; DOI:10.1113/ jphysiol.2006.109512.
113. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2007; 26:1749-60; PMID:17347651; DOI:10.1038/sj.emboj. 7601623.
114. Filomeni G, Desideri E, Cardaci S, Rotilio G, Ciriolo MR. Under the ROS...thiol network is the principal suspect for autophagy commitment. Autophagy 2010; 6:999-1005; PMID:20639698; DOI:10.4161/ auto.6.7.12754.
115. Sarbassov DD, Sabatini DM. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. J Biol Chem 2005; 280:39505-9; PMID:16183647; DOI:10.1074/jbc.M506096200.
116. Cuervo AM. Autophagy and aging: keeping that old broom working. Trends Genet 2008; 24:604-12; PMID:18992957; DOI:10.1016/j.tig.2008.10.002.
117. Hands SL, Proud CG, Wyttenbach A. mTOR's role in aging: protein synthesis or autophagy? Aging (Albany NY) 2009; 1:586-97; PMID:20157541.
118. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011; 18:571-80; PMID:21311563; DOI:10.1038/cdd.2010.191.
119. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 2008; 30:678-88; PMID:18570871; DOI:10.1016/j.molcel. 2008.06.001.
120. Wei Y, Sinha S, Levine B. Dual role of JNK1- mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy 2008; 4:949-51; PMID:18769111.
121. Betin VM, Lane JD. Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis. J Cell Sci 2009; 122:2554-66; PMID:19549685; DOI:10.1242/ jcs.046250.
122. Wirawan E, Vande Walle L, Kersse K, Cornelis S, Claerhout S, Vanoverberghe I, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis 2010; 1:18; PMID:21364619; DOI:10.1038/cddis.2009.16.
123. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006; 8:1124-32; PMID:16998475; DOI:10.1038/ncb1482.