Sirt3, mitochondrial ROS, ageing, and carcinogenesis

International Journal of Molecular Sciences

Volumn 12, Issue 9, 2011, Pages 6226-6239

  Park, Seong Hoon ^a   Ozden, Ozkan ^a   Jiang, Haiyan ^a   Cha, Yong I ^a   Pennington, J Daniel ^a   Aykin Burns, Nukhet ^b   Spitz, Douglas R ^b   Gius, David ^a   Kim, Hyun Seok ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF IOWA   (United States)

Author keywords

Acetylation; Acetylome; Cancer; Carcinogenesis; Mitochondria; MnSOD; Receptor positive breast cancer; Sirt3

Indexed keywords

MANGANESE SUPEROXIDE DISMUTASE; REACTIVE OXYGEN METABOLITE; SIRTUIN 2; SIRTUIN 3; SIRTUIN 4; SIRTUIN 5; SIRTUIN 6; SIRTUIN 7;

ACETYLATION; AGING; BREAST CANCER; BREAST CARCINOGENESIS; CELL METABOLISM; CELL PROTECTION; CELLULAR STRESS RESPONSE; DOWNSTREAM PROCESSING; GENE FUNCTION; HUMAN; METABOLIC REGULATION; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MOLECULAR PATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROCESSING; REVIEW; TUMOR SUPPRESSOR GENE; ANIMAL; BIOLOGICAL MODEL; CARCINOGENESIS; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MITOCHONDRION;

CAENORHABDITIS ELEGANS; MAMMALIA;

AGING; ANIMALS; CARCINOGENESIS; GENE EXPRESSION REGULATION, ENZYMOLOGIC; HUMANS; MITOCHONDRIA; MODELS, BIOLOGICAL; REACTIVE OXYGEN SPECIES; SIRTUIN 3;

EID: 80053214366     PISSN: None     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms12096226     Document Type: Review

References (94)

1. Slane, B.G.; Aykin-Burns, N.; Smith, B.J.; Kalen, A.L.; Goswami, P.C.; Domann, F.E.; Spitz, D.R. Mutation of succinate dehydrogenase subunit C results in increased O 2.-, oxidative stress, and genomic instability. Cancer Res. 2006, 66, 7615-7620.
2. Aykin-Burns, N.; Ahmad, I.M.; Zhu, Y.; Oberley, L.W.; Spitz, D.R. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem. J. 2009, 418, 29-37.
3. Du, C.; Gao, Z.; Venkatesha, V.A.; Kalen, A.L.; Chaudhuri, L.; Spitz, D.R.; Cullen, J.J.; Oberley, L.W.; Goswami, P.C. Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts. Cancer Biol. Ther. 2009, 8, 1962-1971.
4. Mallakin, A.; Sugiyama, T.; Taneja, P.; Matise, L.A.; Frazier, D.P.; Choudhary, M.; Hawkins, G.A.; D'Agostino, R.B., Jr.; Willingham, M.C.; Inoue, K. Mutually Exclusive Inactivation of DMP1 and ARF/p53 in Lung Cancer. Cancer Cell 2007, 12, 381-394.
5. Uren, A.G.; Kool, J.; Matentzoglu, K.; de Ridder, J.; Mattison, J.; van Uitert, M.; Lagcher, W.; Sie, D.; Tanger, E.; Cox, T.; et al. Large-scale mutagenesis in p19ARF-and p53-deficient mice identifies cancer genes and their collaborative networks. Cell 2008, 133, 727-741.
6. Vousden, K.H.; Prives, C. Blinded by the Light: The Growing Complexity of p53. Cell 2009, 137, 413-431.
7. Greger, V.; Passarge, E.; Hopping, W.; Messmer, E.; Horsthemke, B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 1989, 83, 155-158.
8. Baker, S.J.; Markowitz, S.; Fearon, E.R.; Willson, J.K.; Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990, 249, 912-915.
9. Feinberg, A.P.; Johnson, L.A.; Law, D.J.; Kuehn, S.E.; Steenman, M.; Williams, B.R.; Thomas, G.; Boland, C.R.; Rainier, S.; Koi, M. Multiple tumor suppressor genes in multistep carcinogenesis. Tohoku. J. Exp. Med. 1992, 168, 149-152.
10. Sherr, C.J.; McCormick, F. The Rb and p53 pathways in cancer. Cancer Cell 2002, 2, 103-112.
11. Hunter, T. Oncoprotein networks. Cell 1997, 88, 333-346.
12. Clutton, S.M.; Townsend, K.M.; Walker, C.; Ansell, J.D.; Wright, E.G. Radiation induced genomic instability and persisting oxidative stress in primary bone marrow cultures. Carcinogenesis 1996, 17, 1633-1639.
13. Spitz, D.R.; Azzam, E.I.; Li, J.J.; Gius, D. Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev. 2004, 23, 311-322.
14. Duesberg, P. Does aneuploidy or mutation start cancer? Science 2005, 307, 41.
15. Deng, C.X. BRCA1: Cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res. 2006, 34, 1416-1426.
16. Wang, R.H.; Sengupta, K.; Li, C.; Kim, H.S.; Cao, L.; Xiao, C.; Kim, S.; Xu, X.; Zheng, Y.; Chilton, B.; et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008, 14, 312-323.
17. Parada, L.F.; Land, H.; Weinberg, R.A.; Wolf, D.; Rotter, V. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature 1984, 312, 649-651.
18. Taylor, W.R.; Egan, S.E.; Mowat, M.; Greenberg, A.H.; Wright, J.A. Evidence for synergistic interactions between ras, myc and a mutant form of p53 in cellular transformation and tumor dissemination. Oncogene 1992, 7, 1383-1390.
19. Saunders, L.R.; Verdin, E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 2007, 26, 5489-5504.
20. Kim, H.S.; Patel, K.; Muldoon-Jacobs, K.; Bisht, K.S.; Aykin-Burns, N.; Pennington, J.D.; van der Meer, R.; Nguyen, P.; Savage, J.; Owens, K.M.; et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010, 17, 41-52.
21. Gius, D.; Botero, A.; Shah, S.; Curry, H.A. Intracellular oxidation/reduction status in the regulation of transcription factors NF-[kappa] B and AP-1. Toxicol. Lett. 1999, 106, 93-106.
22. Pelicano, H.; Carney, D.; Huang, P. ROS stress in cancer cells and therapeutic implications. Drug Resist. Updat. 2004, 7, 97-110.
23. Valko, M.; Izakovic, M.; Mazur, M.; Rhodes, C.J.; Telser, J. Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem. 2004, 266, 37-56.
24. Spitz, D.R.; Li, G.C. Heat-induced cytotoxicity in H2O2-resistant Chinese hamster fibroblasts. J. Cell Physiol. 1990, 142, 255-260.
25. Sies, H. Role of reactive oxygen species in biological processes. Klin. Wochenschr. 1991, 69, 965-968.
26. Singh, K.K. Mitochondria damage checkpoint, aging, and cancer. Ann. NY Acad. Sci. 2006, 1067, 182-190.
27. Valko, M.; Rhodes, C.J.; Moncol, J.; Izakovic, M.; Mazur, M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 2006, 160, 1-40.
28. Chen, J.; Kadlubar, F.F.; Chen, J.Z. DNA supercoiling suppresses real-time PCR: a new approach to the quantification of mitochondrial DNA damage and repair. Nucleic Acids Res. 2007, 35, 1377-1388.
29. Tanny, J.C.; Dowd, G.J.; Huang, J.; Hilz, H.; Moazed, D. An Enzymatic Activity in the Yeast Sir2 Protein that Is Essential for Gene Silencing. Cell 1999, 99, 735-745.
30. Kaeberlein, M.; McVey, M.; Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999, 13, 2570-2580.
31. Imai, S.; Armstrong, C.M.; Kaeberlein, M.; Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000, 403, 795-800.
32. Landry, J.; Sutton, A.; Tafrov, S.T.; Heller, R.C.; Stebbins, J.; Pillus, L.; Sternglanz, R. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl. Acad. Sci. USA 2000, 97, 5807-5811.
33. Lin, S.J.; Defossez, P.A.; Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000, 289, 2126-2128.
34. North, B.J.; Verdin, E. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 2004, 5, 224.
35. Rogina, B.; Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 2004, 101, 15998-16003.
36. Wood, J.G.; Rogina, B.; Lavu, S.; Howitz, K.; Helfand, S.L.; Tatar, M.; Sinclair, D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004, 430, 686-689.
37. Guarente, L.; Partridge, L.; Wallace, D.C. Molecular Biology of Aging; Cold Spring Harbor Laboratory Press: Woodbury, NY, USA, 2008.
38. Haigis, M.C.; Guarente, L.P. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006, 20, 2913-2921.
39. Finkel, T.; Deng, C.X.; Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 2009, 460, 587-591.
40. Kim, E.J.; Kho, J.H.; Kang, M.R.; Um, S.J. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 2007, 28, 277-290.
41. Smith, K.T.; Workman, J.L. Introducing the acetylome. Nat. Biotechnol. 2009, 27, 917-919.
42. Hallows, W.C.; Albaugh, B.N.; Denu, J.M. Where in the cell is SIRT3?-Functional localization of an NAD+-dependent protein deacetylase. J. Biochem.2008, 411, e11-e13.
43. Chua, K.F.; Mostoslavsky, R.; Lombard, D.B.; Pang, W.W.; Saito, S.; Franco, S.; Kaushal, D.; Cheng, H.L.; Fischer, M.R.; Stokes, N.; et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab. 2005, 2, 67-76.
44. Droge, W.; Schipper, H.M. Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 2007, 6, 361-370.
45. Scher, M.B.; Vaquero, A.; Reinberg, D. SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 2007, 21, 920-928.
46. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 1956, 11, 298-300.
47. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidant in normal physiological function and human disease. Int. J. Biochem. Cell Biol. 2007, 39, 44-84.
48. Buffenstein, R.; Edrey, Y.H.; Yang, T.; Mele, J. The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms. Age (Dordr) 2008, 30, 99-109.
49. Diamond, D.A.; Parsian, A.; Hunt, C.R.; Lofgren, S.; Spitz, D.R.; Goswami, P.C.; Gius, D. Redox factor-1 (Ref-1) mediates the activation of AP-1 in HeLa and NIH 3T3 cells in response to heat shock. J. Biol. Chem. 1999, 274, 16959-16964.
50. Tao, R.; Coleman, M.C.; Pennington, J.D.; Ozden, O.; Park, S.H.; Jiang, H.; Kim, H.S.; Flynn, C.R.; Hill, S.; Hayes McDonald, W.; et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 40, 893-904.
51. Sundaresan, N.R.; Samant, S.A.; Pillai, V.B.; Rajamohan, S.B.; Gupta, M.P. SIRT3 is a stressresponsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol. Cell Biol. 2008, 24, 6384-6401.
52. Hirschey, M.D.; Shimazu, T.; Goetzman, E.; Jing, E.; Schwer, B.; Lombard, D.B.; Grueter, C.A.; Harris, C.; Biddinger, S.; Ilkayeva, O.R.; et al. SIRT3 regulates fatty acid oxidation via reversible enzyme deacetylation. Nature 2010, 464, 121-125.
53. Qiu, X.; Brown, K.; Hirschey, M.D.; Verdin, E.; Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010, 12, 662-667.
54. Someya, S.; Yu, W.; Hallows, W.C.; Xu, J.; Vann, J.M.; Leeuwenburgh, C.; Tanokura, M.; Denu, J.M.; Prolla, T.A. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010, 143, 802-812.
55. Lescai, F.; Blanche, H.; Nebel, A.; Beekman, M.; Sahbatou, M.; Flachsbart, F.; Slagboom, E.; Schreiber, S.; Sorbi, S.; Passarino, G.; Franceschi, C. Human longevity and 11p15. 5: A study in 1321 centenarians. Eur. J. Hum. Genet. 2009, 17, 1515-1519.
56. Hursting, S.D.; Lavigne, J.A.; Berrigan, D.; Perkins, S.N.; Barrett, J.C. Calorie Restriction, Aging, and Cancer Prevention: Mechanisms of Action and Applicability to Humans. Annu. Rev. Med. 2003, 54, 131-152.
57. Sinclair, D.A. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev. 2005, 126, 987-1002.
58. Ershler, W.B.; Longo, D.L. Aging and cancer: issues of basic and clinical science J. Natl. Cancer Inst. 1997, 89, 1489-1497.
59. Nemoto, S.; Fergusson, M.M.; Finkel, T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 2004, 306, 2105-2108.
60. Kouzarides, T. Chromatin Modifications and Their Function. Cell 2007, 128, 693-705.
61. Yang, X.J. Lysine acetylation and the bromodomain: a new partnership for signaling. Bioessays 2004, 26, 1076-1087.
62. Shahbazian, M.D.; Grunstein, M. Of site-specific histone acetylation and deacetylation. Annu. Rev. Biochem. 2007, 76, 75-100.
63. Schwer, B.; Bunkenborg, J.; Verdin, R.O.; Andersen, J.S.; Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl. Acad. Sci. USA 2006, 103, 10224-10229.
64. Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M.L.; Rehman, M.; Walther, T.C.; Olsen, J.V.; Mann, M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009, 325, 834-840.
65. Kim, S.C.; Sprung, R.; Chen, Y.; Xu, Y.; Ball, H.; Pei, J.; Cheng, T.; Kho, Y.; Xiao, H.; Xiao, L.; et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 2006, 23, 607-618.
66. Yang, H.; Baur, J.A.; Chen, A.; Miller, C.; Adams, J.K.; Kisielewski, A.; Howitz, K.T.; Zipkin, R.E.; Sinclair, D.A. Design and synthesis of compounds that extend yeast replicative lifespan. Aging Cell 2007, 6, 35-43.
67. Lombard, D.B.; Alt, F.W.; Cheng, H.L.; Bunkenborg, J.; Streeper, R.S.; Mostoslavsky, R.; Kim, J.; Yancopoulos, G.; Valenzuela, D.; Murphy, A.; et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell Biol. 2007, 27, 8807-8814.
68. Ahn, B.H.; Kim, H.S.; Song, S.; Lee, I.H.; Liu, J.; Vassilopoulos, A.; Deng, C.X.; Finkel, T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl. Acad. Sci. USA 2008, 105, 14447-14452.
69. Ershler, W.B.; Longo, D.L. The biology of aging. Cancer 1997, 80, 1284-1293.
70. Gemma, C.; Vila, J.; Bachstetter, A.; Bickford, P.C. Early inhibition of TNF [alpha] increases 6-hydroxydopamine-induced striatal degeneration. Brain Res. 2007, 1147, 240-247.
71. Dayal, D.; Martin, S.M.; Limoli, C.L.; Spitz, D.R. Hydrogen peroxide mediates the radiationinduced mutator phenotype in mammalian cells. Biochem. J. 2008, 413, 185-191.
72. Schwer, B.; Eckersdorff, M.; Li, Y.; Silva, J.C.; Fermin, D.; Kurtev, M.V.; Giallourakis, C.; Comb, M.J.; Alt, F.W.; Lombard, D.B. Calorie restriction alters mitochondrial protein acetylation. Aging Cell 2009, 8, 604-606.
73. Lombard, D.B. Sirtuins at the breaking point: SIRT6 in DNA repair. Aging (Albany NY) 2009, 1, 12-16.
74. Sundaresan, N.R.; Gupta, M.; Kim, G.; Rajamohan, S.B.; Isbatan, A.; Gupta, M.P. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 2009, 119, 2758-2771.
75. Bell, E.L.; Emerling, B.M.; Ricoult, S.J.; Guarente, L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene 2011, 30, 2986-2996.
76. Finley, L.W.; Carracedo, A.; Lee, J.; Souza, A.; Egia, A.; Zhang, J.; Teruya-Feldstein, J.; Moreira, P.I.; Cardoso, S.M.; Clish, C.B.; Pandolfi, P.P.; Haigis, M.C. SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1 a Destabilization. Cancer Cell 2011, 19, 416-428.
77. Kendrick, A.A.; Choudhury, M.; Rahman, S.M.; McCurdy, C.E.; Friederich, M.; Vanhove, J.L.; Watson, P.A.; Birdsey, N.; Bao, J.; Gius, D.; et al. Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem. J. 2011, 433, 505-514.
78. Sebastian, C.; Mostoslavsky, R. SIRT3 in Calorie Restriction: Can You Hear Me Now? Cell 2010, 143, 667-668.
79. Deng, Y.T.; Huang, H.C.; Lin, J.K. Rotenone induces apoptosis in MCF-7 human breast cancer cell-mediated ROS through JNK and p38 signaling. Mol. Carcinog. 2010, 49, 141-151.
80. Pujana, M.A.; Han, J.D.; Starita, L.M.; Stevens, K.N.; Tewari, M.; Ahn, J.S.; Rennert, G.; Moreno, V.; Kirchhoff, T.; Gold, B.; et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat. Genet. 2007, 39, 1338-1349.
81. Oberley, L.W.; Oberley, T.D. Role of antioxidant enzymes in cell immortalization and transformation. Mol. Cell Biochem. 1988, 84, 147-153.
82. Chen, Y.; Zhang, J.; Lin, Y.; Lei, Q.; Guan, K.L.; Zhao, S.; Xiong, Y. Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep. 12, 534-541.
83. Schumacker, P.T. SIRT3 Controls Cancer Metabolic Reprogramming by Regulating ROS and HIF. Cancer Cell 2011, 19, 299-300.
84. Hallows, W.C.; Lee, S.; Denu, J.M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl. Acad. Sci. USA 2006, 103, 10230-10235.
85. Schlicker, C.; Gertz, M.; Papatheodorou, P.; Kachholz, B.; Becker, C.F.; Steegborn, C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J. Mol. Biol. 2008, 382, 790-801.
86. Cimen, H.; Han, M.J.; Yang, Y.; Tong, Q.; Koc, H.; Koc, E.C. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 2010, 49, 304-311.
87. Yang, Y.; Cimen, H.; Han, M.J.; Shi, T.; Deng, J.H.; Koc, H.; Palacios, O.M.; Montier, L.; Bai, Y.; Tong, Q.; Koc, E.C. NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10. J. Biol. Chem. 2010, 285, 7417-7429.
88. Marfe, G.; Tafani, M.; Indelicato, M.; Sinibaldi-Salimei, P.; Reali, V.; Pucci, B.; Fini, M.; Russo, M.A. Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction. J. Cell Biochem. 2009, 106, 643-650.
89. Allison, S.J.; Milner, J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle 2007, 6, 2669-2677.
90. Veatch, J.R.; McMurray, M.A.; Nelson, Z.W.; Gottschling, D.E. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell 2009, 137, 1247-1258.
91. Chandel, N.S.; McClintock, D.S.; Feliciano, C.E.; Wood, T.M.; Melendez, J.A.; Rodriguez, A.M.; Schumacker, P.T. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1 during hypoxia. A mechanism of O2 sensing. J. Biol. Chem. 2000, 275, 25130-25138.
92. Han, D.; Antunes, F.; Canali, R.; Rettori, D.; Cadenas, E. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 2003, 278, 5557-5563.
93. Kulisz, A.; Chen, N.; Chandel, N.S.; Shao, Z.; Schumacker, P.T. Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am. J. Physiol. Lung Cell Mol. Physiol. 2002, 282, L1324-L1329.
94. Sherr, C.J. Principles of tumor suppression. Cell 2004, 116, 235-246.