Skip to main content
SpringerLink
Log in
Book cover

Geriatric Oncology pp 1–22Cite as

Mitochondria, Oxidative Stress, Cancer, and Aging

  • Living reference work entry
  • First Online:

  • 222 Accesses

Abstract

In human cells, the main source of reactive oxygen species (ROS) and oxidative stress are mitochondria, the organelles where oxidative phosphorylation take place. Although ROS are an inevitable by-products of respiration, they do not necessarily have detrimental effects; low doses of ROS can have beneficial effects on cells, and their production can be finely regulated in mitochondria. Increasing ROS levels and products of the oxidative stress, which occur in aging and age-related disorders, are related to progressive dysfunction of mitochondria, due to damage to mitochondrial DNA or to oxidation and damage of mitochondrial proteins, and are also present in cancer. This chapter focuses on the regulation of ROS production in mitochondria and on the mechanisms that lead to its dysregulation in aging and cancer.

This is a preview of subscription content, log in via an institution.

References

  • Adams L, Franco MC, Estevez AG. Reactive nitrogen species in cellular signaling. Exp Biol Med (Maywood). 2015;240(6):711–7.

    Article  CAS  Google Scholar 

  • Ahlqvist KJ, Hamalainen RH, Yatsuga S, Uutela M, Terzioglu M, Gotz A, et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 2012;15(1):100–9.

    Article  CAS  PubMed  Google Scholar 

  • Aksam EB, Koek A, Kiel JA, Jourdan S, Veenhuis M, van der Klei IJ. A peroxisomal lon protease and peroxisome degradation by autophagy play key roles in vitality of Hansenula polymorpha cells. Autophagy. 2007;3(2):96–105.

    Article  CAS  PubMed  Google Scholar 

  • Ameur A, Stewart JB, Freyer C, Hagstrom E, Ingman M, Larsson NG, Gyllensten U. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 2011;7(3):e1002028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29(10):2570–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beltrami E, Valtorta S, Moresco R, Marcu R, Belloli S, Fassina A, Fazio F, Pelicci P, Giorgio M. The p53-p66Shc apoptotic pathway is dispensable for tumor suppression whereas the p66Shc-generated oxidative stress initiates tumorigenesis. Curr Pharm Des. 2013;19(15):2708–14.

    Article  CAS  PubMed  Google Scholar 

  • Bernardi P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev. 1999;79(4):1127–55.

    CAS  PubMed  Google Scholar 

  • Bernardi P, Rasola A, Forte M, Lippe G. The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol Rev. 2015;95(4):1111–55.

    Article  PubMed  PubMed Central  Google Scholar 

  • Berniakovich I, Trinei M, Stendardo M, Migliaccio E, Minucci S, Bernardi P, Pelicci PG, Giorgio M. p66Shc-generated oxidative signal promotes fat accumulation. J Biol Chem. 2008;283(49):34283–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181–97.

    Article  PubMed  CAS  Google Scholar 

  • Bluher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002;3(1):25–38.

    Article  CAS  PubMed  Google Scholar 

  • Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004;4(10):793–805.

    Article  CAS  PubMed  Google Scholar 

  • Borutaite V, Brown GC. S-nitrosothiol inhibition of mitochondrial complex I causes a reversible increase in mitochondrial hydrogen peroxide production. Biochim Biophys Acta. 2006;1757(5–6):562–6.

    Article  CAS  PubMed  Google Scholar 

  • Bota DA, Van Remmen H, Davies KJ. Modulation of Lon protease activity and aconitase turnover during aging and oxidative stress. FEBS Lett. 2002;532(1–2):103–6.

    Article  CAS  PubMed  Google Scholar 

  • Bragado P, Armesilla A, Silva A, Porras A. Apoptosis by cisplatin requires p53 mediated p38alpha MAPK activation through ROS generation. Apoptosis. 2007;12(9):1733–42.

    Article  CAS  PubMed  Google Scholar 

  • Brown GC. Cell biology. NO says yes to mitochondria. Science. 2003;299(5608):838–9.

    Article  PubMed  Google Scholar 

  • Buzek J, Latonen L, Kurki S, Peltonen K, Laiho M. Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277. Nucleic Acids Res. 2002;30(11):2340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet. 2008;9(8):619–31.

    CAS  PubMed  Google Scholar 

  • Carew JS, Huang P. Mitochondrial defects in cancer. Mol Cancer. 2002;1:9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chan TL, Zhao W, Leung SY, Yuen ST, Cancer Genome P. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003;63(16):4878–81.

    CAS  PubMed  Google Scholar 

  • Cheng Z, Ristow M. Mitochondria and metabolic homeostasis. Antioxid Redox Signal. 2013;19(3):240–2.

    Article  CAS  PubMed  Google Scholar 

  • Cheng CW, Kuo CY, Fan CC, Fang WC, Jiang SS, Lo YK, Wang TY, Kao MC, Lee AY. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 2013;4:e681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chourasia AH, Macleod KF. Tumor suppressor functions of BNIP3 and mitophagy. Autophagy. 2015;11(10):1937–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chourasia AH, Boland ML, Macleod KF. Mitophagy and cancer. Cancer Metab. 2015a;3:4.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chourasia AH, Tracy K, Frankenberger C, Boland ML, Sharifi MN, Drake LE, Sachleben JR, Asara JM, Locasale JW, Karczmar GS, Macleod KF. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep. 2015b;16(9):1145–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA. 2004;101(45):15927–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K, et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell. 2006;126(1):163–75.

    Article  CAS  PubMed  Google Scholar 

  • Cmielova J, Rezacova M. p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]. J Cell Biochem. 2011;112(12):3502–6.

    Article  CAS  PubMed  Google Scholar 

  • Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305(5682):390–2.

    Article  CAS  PubMed  Google Scholar 

  • Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009;325(5937):201–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai DF, Rabinovitch PS, Ungvari Z. Mitochondria and cardiovascular aging. Circ Res. 2012;110(8):1109–24.

    Article  CAS  PubMed  Google Scholar 

  • Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta. 2003;329(1–2):23–38.

    Article  CAS  PubMed  Google Scholar 

  • Dehennaut V, Loison I, Dubuissez M, Nassour J, Abbadie C, Leprince D. DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair. J Biol Chem. 2013;288(15):10254–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delaval E, Perichon M, Friguet B. Age-related impairment of mitochondrial matrix aconitase and ATP-stimulated protease in rat liver and heart. Eur J Biochem. 2004;271(22):4559–64.

    Article  CAS  PubMed  Google Scholar 

  • Desaint S, Luriau S, Aude JC, Rousselet G, Toledano MB. Mammalian antioxidant defenses are not inducible by H2O2. J Biol Chem. 2004;279(30):31157–63.

    Article  CAS  PubMed  Google Scholar 

  • Ding WX, Ni HM, Li M, Liao Y, Chen X, Stolz DB, Dorn GW 2nd, Yin XM. 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(36):27879–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dudkina NV, Eubel H, Keegstra W, Boekema EJ, Braun HP. Structure of a mitochondrial supercomplex formed by respiratory-chain complexes I and III. Proc Natl Acad Sci U S A. 2005;102(9):3225–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab. 2009;10(2):131–8.

    Article  CAS  PubMed  Google Scholar 

  • Erjavec N, Bayot A, Gareil M, Camougrand N, Nystrom T, Friguet B, Bulteau AL. Deletion of the mitochondrial Pim1/Lon protease in yeast results in accelerated aging and impairment of the proteasome. Free Radic Biol Med. 2013;56:9–16.

    Article  CAS  PubMed  Google Scholar 

  • Fan W, Waymire KG, Narula N, Li P, Rocher C, Coskun PE, Vannan MA, Narula J, Macgregor GR, Wallace DC. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science. 2008;319(5865):958–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fato R, Bergamini C, Bortolus M, Maniero AL, Leoni S, Ohnishi T, Lenaz G. Differential effects of mitochondrial complex I inhibitors on production of reactive oxygen species. Biochim Biophys Acta. 2009;1787(5):384–92.

    Article  CAS  PubMed  Google Scholar 

  • Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell. 2011;19(3):416–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flemming A. Cancer: double-pronged approach to combat mutant KRAS. Nat Rev Drug Discov. 2013;12(3):188–9.

    Article  CAS  PubMed  Google Scholar 

  • Francia P, delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E, Pelicci PG, Schiavoni M, Luscher TF, Volpe M, Cosentino F. Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation. 2004;110(18):2889–95.

    Article  CAS  PubMed  Google Scholar 

  • Friguet B, Bulteau AL, Petropoulos I. Mitochondrial protein quality control: implications in ageing. Biotechnol J. 2008;3(6):757–64.

    Article  CAS  PubMed  Google Scholar 

  • Galimov ER. The role of p66shc in oxidative stress and apoptosis. Acta Nat. 2010;2(4):44–51.

    CAS  Google Scholar 

  • Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G. Mitochondrial control of cellular life, stress, and death. Circ Res. 2012;111(9):1198–207.

    Article  CAS  PubMed  Google Scholar 

  • Gang H, Dhingra R, Lin J, Hai Y, Aviv Y, Margulets V, Hamedani M, Thanasupawat T, Leygue E, Klonisch T, Davie JR, Kirshenbaum LA. PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival. J Cell Biol. 2015;210(7):1101–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Genova ML, Baracca A, Biondi A, Casalena G, Faccioli M, Falasca AI, Formiggini G, Sgarbi G, Solaini G, Lenaz G. Is supercomplex organization of the respiratory chain required for optimal electron transfer activity? Biochim Biophys Acta. 2008;1777(7–8):740–6.

    Article  CAS  PubMed  Google Scholar 

  • Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, Roat E, Bertoncelli L, Cooper EL, Cossarizza A. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med. 2011;2011:591356.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gibellini L, Pinti M, Beretti F, Pierri CL, Onofrio A, Riccio M, Carnevale G, De Biasi S, Nasi M, Torelli F, Boraldi F, De Pol A, Cossarizza A. Sirtuin 3 interacts with Lon protease and regulates its acetylation status. Mitochondrion. 2014a;18:76–81.

    Article  CAS  PubMed  Google Scholar 

  • Gibellini L, Pinti M, Boraldi F, Giorgio V, Bernardi P, Bartolomeo R, et al. Silencing of mitochondrial Lon protease deeply impairs mitochondrial proteome and function in colon cancer cells. FASEB J. 2014b;28(12):5122–35.

    Article  CAS  PubMed  Google Scholar 

  • Gibellini L, Bianchini E, De Biasi S, Nasi M, Cossarizza A, Pinti M. Natural compounds modulating mitochondrial functions. Evid Based Complement Alternat Med. 2015a;2015:527209.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gibellini L, Pinti M, Bartolomeo R, De Biasi S, Cormio A, Musicco C, Carnevale G, Pecorini S, Nasi M, De Pol A, Cossarizza A. Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells. Oncotarget. 2015b;6(28):25466–83.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gibellini L, De Biasi S, Nasi M, Iannone A, Cossarizza A, Pinti M. Mitochondrial proteases as emerging pharmacological targets. Curr Pharm Des. 2016;22(18):2679–88.

    Article  CAS  PubMed  Google Scholar 

  • Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122(2):221–33.

    Article  CAS  PubMed  Google Scholar 

  • Giorgio M, Berry A, Berniakovich I, Poletaeva I, Trinei M, Stendardo M, et al. The p66Shc knocked out mice are short lived under natural condition. Aging Cell. 2012;11(1):162–8.

    Article  CAS  PubMed  Google Scholar 

  • Gispert S, Parganlija D, Klinkenberg M, Drose S, Wittig I, Mittelbronn M, et al. Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. Hum Mol Genet. 2013;22(24):4871–87.

    Article  CAS  PubMed  Google Scholar 

  • Griesser M, Boeglin WE, Suzuki T, Schneider C. Convergence of the 5-LOX and COX-2 pathways: heme-catalyzed cleavage of the 5S-HETE-derived di-endoperoxide into aldehyde fragments. J Lipid Res. 2009;50(12):2455–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA. Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem. 2008;283(32):21837–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guarente L. Mitochondria – a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132(2):171–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanson S, Kim E, Deppert W. Redox factor 1 (Ref-1) enhances specific DNA binding of p53 by promoting p53 tetramerization. Oncogene. 2005;24(9):1641–7.

    Article  CAS  PubMed  Google Scholar 

  • Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298–300.

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Garcia D, Wood CD, Castro-Obregon S, Covarrubias L. Reactive oxygen species: a radical role in development? Free Radic Biol Med. 2010;49(2):130–43.

    Article  CAS  PubMed  Google Scholar 

  • Hoppins S. The regulation of mitochondrial dynamics. Curr Opin Cell Biol. 2014;29:46–52.

    Article  CAS  PubMed  Google Scholar 

  • Hoshino A, Okawa Y, Ariyoshi M, Kaimoto S, Uchihashi M, Fukai K, Iwai-Kanai E, Matoba S. Oxidative post-translational modifications develop LONP1 dysfunction in pressure overload heart failure. Circ Heart Fail. 2014;7(3):500–9.

    Article  CAS  PubMed  Google Scholar 

  • Jin SM, Youle RJ. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy. 2013;9(11):1750–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(5):933–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaeberlein M, Burtner CR, Kennedy BK. Recent developments in yeast aging. PLoS Genet. 2007;3(5):e84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kang S, Louboutin JP, Datta P, Landel CP, Martinez D, Zervos AS, Strayer DS, Fernandes-Alnemri T, Alnemri ES. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death Differ. 2013;20(2):259–69.

    Article  CAS  PubMed  Google Scholar 

  • Kao TY, Chiu YC, Fang WC, Cheng CW, Kuo CY, Juan HF, SH W, Lee AY. Mitochondrial Lon regulates apoptosis through the association with Hsp60-mtHsp70 complex. Cell Death Dis. 2015;6:e1642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. Clin Lung Cancer. 2013;14(3):205–14.

    Article  CAS  PubMed  Google Scholar 

  • Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature. 2016;531(7592):110–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JH, Kim HY, Lee YK, Yoon YS, WG X, Yoon JK, Choi SE, Ko YG, Kim MJ, Lee SJ, Wang HJ, Yoon G. Involvement of mitophagy in oncogenic K-Ras-induced transformation: overcoming a cellular energy deficit from glucose deficiency. Autophagy. 2011;7(10):1187–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klotz LO, Schroeder P, Sies H. Peroxynitrite signaling: receptor tyrosine kinases and activation of stress-responsive pathways. Free Radic Biol Med. 2002;33(6):737–43.

    Article  CAS  PubMed  Google Scholar 

  • Kudryavtseva AV, Krasnov GS, Dmitriev AA, Alekseev BY, Kardymon OL, Sadritdinova AF, Fedorova MS, Pokrovsky AV, Melnikova NV, Kaprin AD, Moskalev AA, Snezhkina AV. Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget. 2016;7(29):44879–905.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005;309(5733):481–4.

    Article  CAS  PubMed  Google Scholar 

  • Kurz EU, Lees-Miller SP. DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair (Amst). 2004;3(8–9):889–900.

    Article  CAS  Google Scholar 

  • Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, McConnell JP, Nair KS. Endurance exercise as a countermeasure for aging. Diabetes. 2008;57(11):2933–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larsen NB, Rasmussen M, Rasmussen LJ. Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion. 2005;5(2):89–108.

    Article  CAS  PubMed  Google Scholar 

  • Lebiedzinska-Arciszewska M, Oparka M, Vega-Naredo I, Karkucinska-Wieckowska A, Pinton P, Duszynski J, Wieckowski MR. The interplay between p66Shc, reactive oxygen species and cancer cell metabolism. Eur J Clin Investig. 2015;45(Suppl 1):25–31.

    Article  CAS  Google Scholar 

  • Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999;285(5432):1390–3.

    Article  CAS  PubMed  Google Scholar 

  • Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci USA. 2002a;99(23):14988–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem. 2002b;277(23):20336–42.

    Article  CAS  PubMed  Google Scholar 

  • Lee S, She J, Deng B, Kim J, de Andrade M, Na J, et al. Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease. Oncotarget. 2016;7(28):44211–23.

    Article  PubMed  PubMed Central  Google Scholar 

  • Levine RL. Carbonyl modified proteins in cellular regulation, aging, and disease. Free Radic Biol Med. 2002;32(9):790–6.

    Article  CAS  PubMed  Google Scholar 

  • Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17(4):491–506.

    Article  CAS  PubMed  Google Scholar 

  • Lin YF, Haynes CM. Metabolism and the UPR(mt). Mol Cell. 2016;61(5):677–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu G, Chen X. Regulation of the p53 transcriptional activity. J Cell Biochem. 2006;97(3):448–58.

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. 2012;14(2):177–85.

    Article  PubMed  CAS  Google Scholar 

  • Lu B, Liu T, Crosby JA, Thomas-Wohlever J, Lee I, Suzuki CK. The ATP-dependent Lon protease of Mus musculus is a DNA-binding protein that is functionally conserved between yeast and mammals. Gene. 2003;306:45–55.

    Article  CAS  PubMed  Google Scholar 

  • Luce K, Osiewacz HD. Increasing organismal healthspan by enhancing mitochondrial protein quality control. Nat Cell Biol. 2009;11(7):852–8.

    Article  CAS  PubMed  Google Scholar 

  • Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.

    Article  CAS  PubMed  Google Scholar 

  • Maes H, Van Eygen S, Krysko DV, Vandenabeele P, Nys K, Rillaerts K, Garg AD, Verfaillie T, Agostinis P. BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton. Cell Death Dis. 2014;5:e1127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maltecca F, Aghaie A, Schroeder DG, Cassina L, Taylor BA, Phillips SJ, Malaguti M, Previtali S, Guenet JL, Quattrini A, Cox GA, Casari G. The mitochondrial protease AFG3L2 is essential for axonal development. J Neurosci. 2008;28(11):2827–36.

    Article  CAS  PubMed  Google Scholar 

  • Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458–71.

    Article  CAS  PubMed  Google Scholar 

  • Matsuda S, Nakanishi A, Minami A, Wada Y, Kitagishi Y. Functions and characteristics of PINK1 and Parkin in cancer. Front Biosci (Landmark Ed). 2015;20:491–501.

    Article  Google Scholar 

  • Michiels C, Remacle J. Cytotoxicity of linoleic acid peroxide, malondialdehyde and 4-hydroxynonenal towards human fibroblasts. Toxicology. 1991;66(2):225–34.

    Article  CAS  PubMed  Google Scholar 

  • Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KM, Superti-Furga G, Pawson T, Di Fiore PP, Lanfrancone L, Pelicci PG. Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway. EMBO J. 1997;16(4):706–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402(6759):309–13.

    Article  CAS  PubMed  Google Scholar 

  • Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G. DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell. 2006;17(4):1583–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, Condorelli M, Sica G, De Rosa G, Pelicci P. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci U S A. 2003;100(4):2112–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell. 2015;58(1):123–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Numajiri N, Takasawa K, Nishiya T, Tanaka H, Ohno K, Hayakawa W, et al. On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN). Proc Natl Acad Sci U S A. 2011;108(25):10349–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, et al. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem. 2004;279(24):25689–95.

    Article  CAS  PubMed  Google Scholar 

  • Pacini S, Pellegrini M, Migliaccio E, Patrussi L, Ulivieri C, Ventura A, Carraro F, Naldini A, Lanfrancone L, Pelicci P, Baldari CT. p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells. Mol Cell Biol. 2004;24(4):1747–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palikaras K, Lionaki E, Tavernarakis N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature. 2015;521(7553):525–8.

    Article  CAS  PubMed  Google Scholar 

  • Park CB, Larsson NG. Mitochondrial DNA mutations in disease and aging. J Cell Biol. 2011;193(5):809–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel RP, McAndrew J, Sellak H, White CR, Jo H, Freeman BA, Darley-Usmar VM. Biological aspects of reactive nitrogen species. Biochim Biophys Acta. 1999;1411(2–3):385–400.

    Article  CAS  PubMed  Google Scholar 

  • Persons DL, Yazlovitskaya EM, Pelling JC. Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. J Biol Chem. 2000;275(46):35778–85.

    Article  CAS  PubMed  Google Scholar 

  • Pinti M, Gibellini L, Guaraldi G, Orlando G, Gant TW, Morselli E, Nasi M, Salomoni P, Mussini C, Cossarizza A. Upregulation of nuclear-encoded mitochondrial LON protease in HAART-treated HIV-positive patients with lipodystrophy: implications for the pathogenesis of the disease. AIDS. 2010;24(6):841–50.

    Article  CAS  PubMed  Google Scholar 

  • Pinti M, Gibellini L, De Biasi S, Nasi M, Roat E, O’Connor JE, Cossarizza A. Functional characterization of the promoter of the human Lon protease gene. Mitochondrion. 2011;11(1):200–6.

    Article  CAS  PubMed  Google Scholar 

  • Pinti M, Gibellini L, Liu Y, Xu S, Lu B, Cossarizza A. Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer. Cell Mol Life Sci. 2015;72(24):4807–24.

    Article  CAS  PubMed  Google Scholar 

  • Powers SK, Duarte J, Kavazis AN, Talbert EE. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol. 2010;95(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  • Quiros PM, Espanol Y, Acin-Perez R, Rodriguez F, Barcena C, Watanabe K, Calvo E, Loureiro M, Fernandez-Garcia MS, Fueyo A, Vazquez J, Enriquez JA, Lopez-Otin C. ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep. 2014;8(2):542–56.

    Article  CAS  PubMed  Google Scholar 

  • Quiros PM, Langer T, Lopez-Otin C. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol. 2015;16(6):345–59.

    Article  CAS  PubMed  Google Scholar 

  • Rao VK, Carlson EA, Yan SS. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta. 2014;1842(8):1267–72.

    Article  CAS  PubMed  Google Scholar 

  • Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24(5):981–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response. 2014;12(2):288–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salet C, Moreno G, Ricchelli F, Bernardi P. Singlet oxygen produced by photodynamic action causes inactivation of the mitochondrial permeability transition pore. J Biol Chem. 1997;272(35):21938–43.

    Article  CAS  PubMed  Google Scholar 

  • Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M, Santini D, Ceccarelli C, Chieco P, Bonafe M. p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells. 2007;25(3):807–15.

    Article  CAS  PubMed  Google Scholar 

  • 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(7):1749–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwarten M, Mohrluder J, Ma P, Stoldt M, Thielmann Y, Stangler T, Hersch N, Hoffmann B, Merkel R, Willbold D. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy. 2009;5(5):690–8.

    Article  CAS  PubMed  Google Scholar 

  • Seemann S, Hainaut P. Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity. Oncogene. 2005;24(24):3853–63.

    Article  CAS  PubMed  Google Scholar 

  • Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326(5949):140–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Semenza GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta. 2016;1863(3):382–91.

    Article  CAS  PubMed  Google Scholar 

  • Seo YR, Kelley MR, Smith ML. Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci U S A. 2002;99(22):14548–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shokolenko IN, Wilson GL, Alexeyev MF. Aging: a mitochondrial DNA perspective, critical analysis and an update. World J Exp Med. 2014;4(4):46–57.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sies H. Strategies of antioxidant defense. Eur J Biochem. 1993;215(2):213–9.

    Article  CAS  PubMed  Google Scholar 

  • Soliman MA, Abdel Rahman AM, Lamming DW, Birsoy K, Pawling J, Frigolet ME, Lu H, Fantus IG, Pasculescu A, Zheng Y, Sabatini DM, Dennis JW, Pawson T. The adaptor protein p66Shc inhibits mTOR-dependent anabolic metabolism. Sci Signal. 2014;7(313):ra17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun XZ, Vinci C, Makmura L, Han S, Tran D, Nguyen J, Hamann M, Grazziani S, Sheppard S, Gutova M, Zhou F, Thomas J, Momand J. Formation of disulfide bond in p53 correlates with inhibition of DNA binding and tetramerization. Antioxid Redox Signal. 2003;5(5):655–65.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki YJ, Carini M, Butterfield DA. Protein carbonylation. Antioxid Redox Signal. 2010;12(3):323–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF. GADD45 proteins: central players in tumorigenesis. Curr Mol Med. 2012;12(5):634–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10(4):267–77.

    Article  CAS  PubMed  Google Scholar 

  • Thomas RE, Andrews LA, Burman JL, Lin WY, Pallanck LJ. PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet. 2014;10(5):e1004279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Trinei M, Giorgio M, Cicalese A, Barozzi S, Ventura A, Migliaccio E, et al. A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene. 2002;21(24):3872–8.

    Article  CAS  PubMed  Google Scholar 

  • Trinei M, Berniakovich I, Beltrami E, Migliaccio E, Fassina A, Pelicci P, Giorgio M. P66Shc signals to age. Aging (Albany NY). 2009;1(6):503–10.

    Article  CAS  Google Scholar 

  • Ueno M, Masutani H, Arai RJ, Yamauchi A, Hirota K, Sakai T, Inamoto T, Yamaoka Y, Yodoi J, Nikaido T. Thioredoxin-dependent redox regulation of p53-mediated p21 activation. J Biol Chem. 1999;274(50):35809–15.

    Article  CAS  PubMed  Google Scholar 

  • Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Nature. 2012;491(7424):374–83.

    Article  CAS  PubMed  Google Scholar 

  • Veeramani S, Yuan TC, Lin FF, Lin MF. Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells. Oncogene. 2008;27(37):5057–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, et al. Somatic mutations of the Parkinson’s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet. 2010;42(1):77–82.

    Article  CAS  PubMed  Google Scholar 

  • Velu CS, Niture SK, Doneanu CE, Pattabiraman N, Srivenugopal KS. Human p53 is inhibited by glutathionylation of cysteines present in the proximal DNA-binding domain during oxidative stress. Biochemistry. 2007;46(26):7765–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vina J, Borras C, Abdelaziz KM, Garcia-Valles R, Gomez-Cabrera MC. The free radical theory of aging revisited: the cell signaling disruption theory of aging. Antioxid Redox Signal. 2013;19(8):779–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voos W. Chaperone-protease networks in mitochondrial protein homeostasis. Biochim Biophys Acta. 2013;1833(2):388–99.

    Article  CAS  PubMed  Google Scholar 

  • Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer. 2002;2(8):594–604.

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 2014a;15(5):566–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y, Williams EG, Dubuis S, Mottis A, Jovaisaite V, Houten SM, Argmann CA, Faridi P, Wolski W, Kutalik Z, Zamboni N, Auwerx J, Aebersold R. Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell. 2014b;158(6):1415–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong Y, Wang M, Zhao J, Han Y, Jia L. Sirtuin 3: a Janus face in cancer (review). Int J Oncol. 2016;49(6):2227–35.

    Article  PubMed  Google Scholar 

  • Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19(5):757–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zarse K, Schmeisser S, Groth M, Priebe S, Beuster G, Kuhlow D, Guthke R, Platzer M, Kahn CR, Ristow M. Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab. 2012;15(4):451–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000;408(6811):433–9.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Liao W, Yang J, Ma K, Li X, Wang Y, Wang D, Wang L, Zhang Y, Yin Y, Zhao Y, Zhu WG. FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway. Autophagy. 2012;8(12):1712–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study has been supported by FAR-UNIMORE (Fondo Ateneo per la Ricerca) grant to MP. Sara De Biasi is an International Society for Advancement in Cytometry (ISAC) Marylou Ingram Scholar.

Author information

Authors and Affiliations

  1. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Simone Pecorini

  2. Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Lara Gibellini, Elena Bianchini & Milena Nasi

  3. Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, Italy

    Andrea Cossarizza

  4. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Sara De Biasi & Marcello Pinti

Authors
  1. Simone Pecorini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lara Gibellini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara De Biasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elena Bianchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Milena Nasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Cossarizza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcello Pinti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcello Pinti .

Editor information

Editors and Affiliations

  1. Senior Adult Oncology Program, Moffitt Cancer Center, Tampa, Florida, USA

    Martine Extermann

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

    Tamas Fulop

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Pecorini, S. et al. (2018). Mitochondria, Oxidative Stress, Cancer, and Aging. In: Extermann, M. (eds) Geriatric Oncology . Springer, Cham. https://doi.org/10.1007/978-3-319-44870-1_80-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-44870-1_80-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-44870-1

  • Online ISBN: 978-3-319-44870-1

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation