Skip to main content

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

Abstract

Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  • Addabbo F, Montagnani M, Goligorsky MS (2009) Mitochondria and reactive oxygen species. Hypertension 53:885–892. doi:10.1161/HYPERTENSIONAHA.109.130054

    PubMed  Article  CAS  Google Scholar 

  • Ahn B, Harrigan JA, Indig FE, Wilson DM III, Bohr VA (2004) Regulation of WRN helicase activity in human base excision repair. J Biol Chem 279:53465–53474. doi:10.1074/jbc.M409624200

    PubMed  Article  CAS  Google Scholar 

  • Alcaín FJ, Villalba JM (2009) Sirtuin activators. Expert Opin Ther Pathol 19:403–414. doi:10.1038/nature01960

    Article  CAS  Google Scholar 

  • Amaral S, Ramalho-Santos J (2009) Aging, mitochondria and male reproductive function. Curr Aging Sci 2:165–173. doi:10.2174/1874609810902030165

    PubMed  Article  CAS  Google Scholar 

  • Ambrose M, Goldstine JV, Gatti RA (2007) Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet 16:2154–2164. doi:10.1093/hmg/ddm166

    PubMed  Article  CAS  Google Scholar 

  • Auerbach AD (2009) Fanconi anemia and its diagnosis. Mutat Res 668:4–10. doi:10.1016/j.mrfmmm.2009.01.013

    PubMed  CAS  Google Scholar 

  • Bambrick LL, Fiskum G (2008) Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res 1188:9–16. doi:10.1016/j.brainres.2007.10.045

    PubMed  Article  CAS  Google Scholar 

  • Barber T, Borrás E, Torres L, García C, Cabezuelo F, Lloret A, Pallardó FV, Viña JR (2000) Vitamin A deficiency causes oxidative damage to liver mitochondria in rats. Free Radic Biol Med 29:1–7. doi:10.1016/S0891-5849(00)00283-5

    PubMed  Article  CAS  Google Scholar 

  • Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ II, Wynshaw-Boris A, Levine RL (1999) Loss of the Ataxia-Telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci USA 96:9915–9919 PMID: 10449794 PMCID: PMC22310

    PubMed  Article  CAS  Google Scholar 

  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342. doi:10.1038/nature05354

    PubMed  Article  CAS  Google Scholar 

  • Bersu ET, Ahmad FJ, Schwei MJ, Baas PW (1998) Cytoplasmic abnormalities in cultured cerebellar neurons from the trisomy 16 mouse. Brain Res Dev Brain Res 109:115–120. doi:10.1016/S0165-3806(98)00070-4

    PubMed  Article  CAS  Google Scholar 

  • Bogliolo M, Borghini S, Abbondandolo A, Degan P (2002) Alternative metabolic pathways for energy supply and resistance to apoptosis in Fanconi anaemia. Mutagenesis 17:25–30. doi:10.1093/mutage/17.1.25

    PubMed  Article  CAS  Google Scholar 

  • Borrás C, Sastre J, García-Sala D, Lloret A, Pallardó FV, Viña J (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34:546–552. doi:10.1016/S0891-5849(02)01356-4

    PubMed  Article  CAS  Google Scholar 

  • Borrás C, Gambini J, López-Grueso R, Pallardó FV, Viña J (2009) Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochim Biophys Acta. doi:10.1016/j.bbadis.2009.09.007

  • Boveris A, Navarro A (2008) Brain mitochondrial dysfunction in aging. IUBMB Life 60:308–314. doi:10.1002/iub.46

    PubMed  Article  CAS  Google Scholar 

  • Browne SE, Roberts LJ II, Dennery PA, Doctrow SR, Beal MF, Barlow C, Levine RL (2004) Treatment with a catalytic antioxidant corrects the neurobehavioral defect in Ataxia-Telangiectasia mice. Free Radic Biol Med 36:938–942. doi:10.1016/j.freeradbiomed.2004.01.003

    PubMed  Article  CAS  Google Scholar 

  • Bukowy Z, Harrigan JA, Ramsden DA, Tudek B, Bohr VA, Stevnsner T (2008) WRN exonuclease activity is blocked by specific oxidatively induced base lesions positioned in either DNA strand. Nucleic Acids Res 36:4975–4987. doi:10.1093/nar/gkn468

    PubMed  Article  CAS  Google Scholar 

  • Calabrese V, Scapagnini G, Ravagna A, Colombrita C, Spadaro F, Butterfield DA, Giuffrida Stella AM (2004) Increased expression of heat shock proteins in rat brain during aging: relationship with mitochondrial function and glutathione redox state. Mech Ageing Dev 125:325–335. doi:10.1016/j.mad.2004.01.003

    PubMed  Article  CAS  Google Scholar 

  • Capell BC, Tlougan BE, Orlow SJ (2009) From the rarest to the most common: Insights from progeroid syndromes into skin cancer and aging. J Invest Dermatol 129:2340–2350. doi:10.1038/jid.2009.103

    PubMed  Article  CAS  Google Scholar 

  • Capone G, Kim P, Jovanovich S, Payne L, Freund L, Welch K, Miller E, Trush M (2002) Evidence for increased mitochondrial superoxide production in Down Syndrome. Life Sci 70:2885–2895. doi:10.1016/S0024-3205(02)01538-2

    PubMed  Article  CAS  Google Scholar 

  • Cassano P, Sciancalepore AG, Pesce V, Fluck M, Hoppeler H, Calvani M, Mosconi L, Cantatore P, Gadaleta MN (2006) Acetyl-l-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis. Biochim Biophys Acta 1757:1421–1428. doi:10.1016/j.bbabio.2006.05.019

    PubMed  Article  CAS  Google Scholar 

  • Chen L, Na R, Gu M, Salmon AB, Liu Y, Liang H, Qi W, Van Remmen H, Richardson A, Ran Q (2008) Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice. Aging Cell 7:866–878. doi:10.1111/j.1474-9726.2008.00432

    PubMed  Article  CAS  Google Scholar 

  • Cheng WH, Muftuoğlu M, Bohr VA (2007) Werner syndrome protein: functions in the response to DNA damage and replication stress in S-phase. Exp Gerontol 42:871–878. doi:10.1016/j.exger.2007.04.011

    PubMed  Article  CAS  Google Scholar 

  • Conti A, Fabbrini F, D’Agostino P, Negri R, Greco D, Genesio R, D’Armiento M, Olla C, Paladini D, Zannini M, Nitsch L (2007) Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genomics 8:268. doi:10.1186/1471-2164-8-268

    PubMed  Article  CAS  Google Scholar 

  • Cox AG, Winterbourn CC, Hampton MB (2010) Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling. Biochem J 425:313–325. doi:10.1042/BJ20091541

    Article  CAS  Google Scholar 

  • Craig EA, Kramer J, Shilling J, Werner-Washburne M, Holmes S, Kosic-Smithers J, Nicolet CM (1989) SSC1, an essential member of the yeast HSP70 multigene family, encodes a mitochondrial protein. Mol Cell Biol 9:3000–3008. doi:0270-7306/89/073000-09$02.00/0

    PubMed  CAS  Google Scholar 

  • Csiszar A, Labinskyy N, Podlutsky A, Kaminski PM, Wolin MS, Zhang C, Mukhopadhyay P, Pacher P, Hu F, de Cabo R, Ballabh P, Ungvari Z (2008) Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol Heart Circ Physiol 294:H2721–H2735. doi:10.1152/ajpheart.00235.2008

    PubMed  Article  CAS  Google Scholar 

  • D’Amelio P, Cristofaro MA, Tamone C, Morra E, Di Bella S, Isaia G, Grimaldi A, Gennero L, Gariboldi A, Ponzetto A, Pescarmona GP, Isaia GC (2008) Role of iron metabolism and oxidative damage in postmenopausal bone loss. Bone 43:1010–1015. doi:10.1016/j.bone.2008.08.107

    PubMed  Article  CAS  Google Scholar 

  • Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS (2009) Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119:2789–2797. doi:10.1161/CIRCULATIONAHA.108.822403

    PubMed  Article  CAS  Google Scholar 

  • Davis T, Kipling D (2009) Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of Ataxia Telangiectasia and Werner syndrome fibroblasts. Biogerontology 10:253–266. doi:10.1007/s10522-008-9179-x

    PubMed  Article  CAS  Google Scholar 

  • Davis JE, Voisine C, Craig EA (1999) Intragenic suppressors of Hsp70 mutants: interplay between the ATPase- and peptide-binding domains. Proc Natl Acad Sci USA 96:9269–9276. doi:9269-9276

    PubMed  Article  CAS  Google Scholar 

  • de la Asuncion JG, Millan A, Pla R, Bruseghini L, Esteras A, Pallardó FV, Sastre J, Viña J (1996) Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA. FASEB J 10:333–338. doi:0892-6638/96/0010-0333

    PubMed  Google Scholar 

  • Deocaris CC, Kaul SC, Wadhwa R (2008) From proliferative to neurological role of an hsp70 stress chaperone, mortalin. Biogerontology 9:391–403. doi:10.1007/s10522-008-9174-2

    PubMed  Article  CAS  Google Scholar 

  • Deschênes F, Massip L, Garand C, Lebel M (2005) In vivo misregulation of genes involved in apoptosis, development and oxidative stress in mice lacking both functional Werner syndrome protein and poly(ADP-ribose) polymerase-1. Hum Mol Genet 14:3293–3308. doi:10.1093/hmg/ddi362

    PubMed  Article  CAS  Google Scholar 

  • Druzhyna N, Nair RG, LeDoux SP, Wilson GL (1998) Defective repair of oxidative damage in mitochondrial DNA in Down’s syndrome. Mutat Res 409:81–89. doi:10.1016/S0921-8777(98)00042-1

    PubMed  CAS  Google Scholar 

  • Du W, Adam Z, Rani R, Zhang X, Pang Q (2008) Oxidative stress in Fanconi anemia hematopoiesis and disease progression. Antioxid Redox Signal 10:1909–1921. doi:10.1089/ars.2008.2129

    PubMed  Article  CAS  Google Scholar 

  • Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS (2007) Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. J Clin Invest 117:2723–2734. doi:10.1172/JCI31604

    PubMed  Article  CAS  Google Scholar 

  • Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10:131–138. doi:10.1016/j.cmet.2009.06.010

    PubMed  Article  CAS  Google Scholar 

  • Epstein CJ, Martin GM, Schultz AL, Motulsky AG (1966) Werner’s syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45:177–221 PMID: 5327241

    CAS  Google Scholar 

  • Erker L, Schubert R, Yakushiji H, Barlow C, Larson D, Mitchell JB, Wynshaw-Boris A (2005) Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor. Hum Mol Genet 14:1699–1708. doi:10.1093/hmg/ddi181

    PubMed  Article  CAS  Google Scholar 

  • Fearon IM, Faux SP (2009) Oxidative stress and cardiovascular disease: novel tools give (free) radical insight. J Mol Cell Cardiol 47:372–381. doi:10.1016/j.yjmcc.2009.05.013

    PubMed  Article  CAS  Google Scholar 

  • Fu X, Wan S, Lyu YL, Liu LF, Qi H (2008) Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS One 3:e2009. doi:10.1371/journal.pone.0002009

    PubMed  Article  CAS  Google Scholar 

  • Fukui H, Moraes CT (2009) Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum Mol Genet 18:1028–1036. doi:10.1093/hmg/ddn437

    PubMed  Article  CAS  Google Scholar 

  • Gadaleta MN, Petruzzella V, Renis M, Fracasso F, Cantatore P (1990) Reduced transcription of mitochondrial DNA in the senescent rat. Tissue dependence and effect of L-carnitine. Eur J Biochem 187:501–506. doi:10.1111/j.1432-1033.1990.tb15331.x

    PubMed  Article  CAS  Google Scholar 

  • Gadaleta MN, Cormio A, Pesce V, Lezza AMS, Cantatore P (1998) Aging and mitochondria. Biochimie 80:863–870. doi:10.1016/S0300-9084(00)88881-1

    PubMed  Article  CAS  Google Scholar 

  • Ghosh A, Rossi ML, Aulds J, Croteau D, Bohr VA (2009) Telomeric D-loops containing 8-oxo-2′-deoxyguanosine are preferred substrates for Werner and Bloom Syndrome helicases and are bound by POT1. J Biol Chem 284:31074–31084. doi:10.1074/jbc.M109.027532

    PubMed  Article  CAS  Google Scholar 

  • Graier WF, Malli R, Kostner GM (2009) Mitochondrial protein phosphorylation: instigator or target of lipotoxicity? Trends Endocrinol Metab 20:186–913. doi:10.1016/j.tem.2009.01.004

    PubMed  Article  CAS  Google Scholar 

  • Green AM, Kupfer GM (2009) Fanconi anemia. Hematol Oncol Clin N Am 23:193–214. doi:10.1016/j.hoc.2009.01.008

    Article  Google Scholar 

  • Grillari J, Katinger H, Voglauer R (2007) Contributions of DNA interstrand cross-links to aging of cells and organisms. Nucleic Acids Res 35:7566–7576. doi:10.1093/nar/gkm1065

    PubMed  Article  CAS  Google Scholar 

  • Groner Y, Elroy-Stein O, Avraham KB, Schickler M, Knobler H, Minc-Golomb D, Bar-Peled O, Yarom R, Rotshenker S (1994) Cell damage by excess CuZnSOD and Down’s syndrome. Biomed Pharmacother 48:231–240. doi:10.1016/0753-3322(94)90138-4

    PubMed  Article  CAS  Google Scholar 

  • Halliwell B, Gutteridge J (2007) Free radicals in biology and medicine, 4th edn. Oxford University Press, Oxford ISBN13: 978-0-19-856869-8

    Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300 PMID: 13332224

    PubMed  CAS  Google Scholar 

  • Harrigan JA, Piotrowski J, Di Noto L, Levine RL, Bohr VA (2007) Metal-catalyzed oxidation of the Werner syndrome protein causes loss of catalytic activities and impaired protein-protein interactions. J Biol Chem 282:36403–36411. doi:10.1074/jbc.M706107200

    PubMed  Article  CAS  Google Scholar 

  • Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88. doi:10.1146/annurev.pharmtox.45.120403.095857

    PubMed  Article  CAS  Google Scholar 

  • Herrera MD, Mingorance C, Rodríguez-Rodríguez C, Alvarez de Sotomayor M (2009) Endothelial dysfunction and aging: an update. Ageing Res Rev. doi:10.1016/j.arr.2009.07.002

  • Hudson EK, Hogue BA, Souza-Pinto NC, Croteau DL, Anson RM, Bohr VA, Hansford RG (1998) Age-associated change in mitochondrial DNA damage. Free Radic Res 29:573–579. doi:10.1080/10715769800300611

    PubMed  Article  CAS  Google Scholar 

  • Jang YC, Lustgarten MS, Liu Y, Muller FL, Bhattacharya A, Liang H, Salmon AB, Brooks SV, Larkin L, Hayworth CR, Richardson A, Van Remmen H (2009) Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J. doi:fj.09-146308v2

  • Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B (2008) Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging. J Agric Food Chem 56:10544–10551. doi:10.1021/jf802279h

    PubMed  Article  CAS  Google Scholar 

  • Jung T, Catalgol B, Grune T (2009) The proteasomal system. Mol Aspects Med 30:191–296. doi:10.1016/j.mam.2009.04.001

    PubMed  Article  CAS  Google Scholar 

  • Kamath-Loeb AS, Shen JC, Loeb LA, Fry M (1998) Werner syndrome protein. II. Characterization of the integral 3′→5′ DNA exonuclease. J Biol Chem 273:34145–34150. doi:10.1074/jbc.273.51.34145

    PubMed  Article  CAS  Google Scholar 

  • Kedziora J, Bartosz G (1988) Down’s syndrome: a pathology involving the lack of balance of reactive oxygen species. Free Radic Biol Med 4:317–330. doi:10.1016/0891-5849(88)90052-4

    PubMed  Article  CAS  Google Scholar 

  • Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, Chung HY, Mattson MP, Lee J (2008) Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem 283:14497–14505. doi:10.1074/jbc.M708373200

    PubMed  Article  CAS  Google Scholar 

  • Kimura K, Tanaka N, Nakamura N, Takano S, Ohkuma S (2007) Knockdown of mitochondrial heat shock protein 70 promotes progeria-like phenotypes in Caenorhabditis elegans. J Biol Chem 282:5910–5918. doi:10.1074/jbc.M609025200

    PubMed  Article  CAS  Google Scholar 

  • Koepke JI, Wood CS, Terlecky LJ, Walton PA, Terlecky SR (2008) Progeric effects of catalase inactivation in human cells. Toxicol Appl Pharmacol 232:99–108. doi:10.1016/j.taap.2008.06.004

    PubMed  Article  CAS  Google Scholar 

  • Kohda Y, Gemba M (2005) Cephaloridine induces translocation of protein kinase C delta into mitochondria and enhances mitochondrial generation of free radicals in the kidney cortex of rats causing renal dysfunction. J Pharmacol Sci 98:49–57. doi:10.1254/jphs.FP0040926

    PubMed  Article  CAS  Google Scholar 

  • Koltover VK (2009) Bioantioxidants: the systems reliability standpoint. Toxicol Ind Health 25:295–299. doi:10.1177/0748233709103029

    PubMed  Article  CAS  Google Scholar 

  • Kruyt FA, Hoshino T, Liu JM, Joseph P, Jaiswal AK, Youssoufian H (1998) Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase. Blood 92:3050–3056. doi:0006-4971/98/9209-0069$3.00/0

    PubMed  CAS  Google Scholar 

  • Kyng KJ, May A, Kølvraa S, Bohr VA (2003) Gene expression profiling in Werner syndrome closely resembles that of normal aging. Proc Natl Acad Sci USA 100:12259–12264. doi:10.1073/pnas.2130723100

    PubMed  Article  CAS  Google Scholar 

  • Lambert AJ, Brand MD (2009) Reactive oxygen species production by mitochondria. Methods Mol Biol 554:165–181. doi:10.1007/978-1-59745-521-3_11

    PubMed  Article  CAS  Google Scholar 

  • Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9:759–769. doi:10.1038/nrm2514

    PubMed  Article  CAS  Google Scholar 

  • Lesnefsky EJ, Minkler P, Hoppel CL (2009) Enhanced modification of cardiolipin during ischemia in the aged heart. J Mol Cell Cardiol 46:1008–1015. doi:10.1016/j.yjmcc.2009.03.007

    Article  CAS  Google Scholar 

  • Levitus M, Joenje H, de Winter JP (2006) The Fanconi anemia pathway of genomic maintenance. Cell Oncol 28:3–29

    PubMed  CAS  Google Scholar 

  • Li H, Dryhurst G (2001) Oxidative metabolites of 5-S-cysteinyldopamine inhibit the pyruvate dehydrogenase complex. J Neural Transm 108:1363–1374. doi:10.1007/s007020100013

    PubMed  Article  CAS  Google Scholar 

  • Li Y, Li HZ, Hu P, Deng J, Banoei MM, Sharma LK, Bai Y (2009) Generation and bioenergetic analysis of cybrids containing mitochondrial DNA from mouse skeletal muscle during aging. Nucleic Acids Res. doi:10.1093/nar/gkp1162

  • Liesa M, Palacín M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89:799–845. doi:10.1152/physrev.00030.2008

    PubMed  Article  CAS  Google Scholar 

  • Liu J (2008) The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res 33:194–203. doi:10.1007/s11064-007-9403-0

    PubMed  Article  CAS  Google Scholar 

  • Ljubicic V, Menzies KJ, Hood DA (2009) Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle. Mech Ageing Dev 131:79–88. doi:10.1016/j.mad.2009.12.004

    PubMed  Article  CAS  Google Scholar 

  • Lloret A, Calzone R, Dunster C, Manini P, d’Ischia M, Degan P, Kelly FJ, Pallardó FV, Zatterale A, Pagano G (2008a) Different patterns of in vivo prooxidant states in a set of cancer- or ageing-related genetic diseases. Free Radic Biol Med 44:495–503. doi:10.1016/j.freeradbiomed.2007.10.046

    PubMed  Article  CAS  Google Scholar 

  • Lloret A, Badía MC, Mora NJ, Ortega A, Pallardó FV, Alonso MD, Atamna H, Viña J (2008b) Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer’s disease. Free Radic Biol Med 44:2019–2025. doi:10.1016/j.freeradbiomed.2008.02.017

    PubMed  Article  CAS  Google Scholar 

  • Long J, Wang X, Gao H, Liu Z, Liu C, Miao M, Cui X, Packer L, Liu J (2007) D-galactose toxicity in mice is associated with mitochondrial dysfunction: protecting effects of mitochondrial nutrient R-alpha-lipoic acid. Biogerontology 8:373–381. doi:10.1007/s10522-007-9081-y

    PubMed  Article  CAS  Google Scholar 

  • López-Lluch G, Irusta PM, Navas P, de Cabo R (2009) Mitochondrial biogenesis and healthy aging. Exp Gerontol 43:813–819. doi:10.1016/j.exger.2008.06.014

    Article  CAS  Google Scholar 

  • Lott IT, Head E, Doran E, Busciglio J (2006) Beta-amyloid, oxidative stress and Down syndrome. Curr Alzheimer Res 3:521–528. doi:10.2174/156720506779025305

    PubMed  Article  CAS  Google Scholar 

  • Madiraju P, Pande SV, Prentki M, Madiraju SRM (2009) Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation. Epigenetics 4:399–403 IDS Number: 491OV – ISSN: 1559-2294

    PubMed  Article  CAS  Google Scholar 

  • Marques C, Guo W, Pereira P, Taylor A, Patterson C, Evans PC, Shang F (2006) The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J 20:741–743. doi:10.1096/fj.05-5080fje

    PubMed  CAS  Google Scholar 

  • Massip L, Garand C, Turaga RV, Deschênes F, Thorin E, Lebel M (2006) Increased insulin, triglycerides, reactive oxygen species, and cardiac fibrosis in mice with a mutation in the helicase domain of the Werner syndrome gene homologue. Exp Gerontol 41:157–168. doi:10.1016/j.exger.2005.10.011

    PubMed  Article  CAS  Google Scholar 

  • Massip L, Garand C, Labbé A, Perreault E, Turaga RVN, Bohr VA, Lebel M (2009) Depletion of WRN protein causes RACK1 to activate several protein kinase C isoforms. Oncogene. doi:10.1038/onc.2009.443

  • Massip L, Garand C, Paquet E, Cogger VC, Oreilly J, Tworek L, Hatherell A, Taylor CG, Thorin E, Zahradka P, Le Couteur DG, Lebel M (2010) Vitamin C restores healthy aging in a mouse model for Werner Syndrome. FASEB J 24:158–172. doi:10.1096/fj.09-137133

    PubMed  Article  CAS  Google Scholar 

  • Mavrou A, Tsangaris GT, Roma E, Kolialexi A (2008) The ATM gene and ataxia telangiectasia. Anticancer Res 28:401–405

    PubMed  CAS  Google Scholar 

  • McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 10:63–79 PMID: 2520283

    CAS  Google Scholar 

  • Migliore L, Molinu S, Naccarati A, Mancuso M, Rocchi A, Siciliano G (2004) Evaluation of cytogenetic and DNA damage in mitochondrial disease patients: effects of coenzyme Q10 therapy. Mutagenesis 19:43–49. doi:10.1093/mutage/geg036

    PubMed  Article  CAS  Google Scholar 

  • Minamiyama Y, Takemura S, Bito Y, Shinkawa H, Tsukioka T, Nakahira A, Suehiro S, Okada S (2008) Supplementation of alpha-tocopherol improves cardiovascular risk factors via the insulin signalling pathway and reduction of mitochondrial reactive oxygen species in type II diabetic rats. Free Radic Res 42:261–271. doi:10.1080/10715760801898820

    PubMed  Article  CAS  Google Scholar 

  • Miquel J, Fleming JE (1984) A two-step hypothesis on the mechanisms of in vitro cell aging: cell differentiation followed by intrinsic mitochondrial mutagenesis. Exp Gerontol 19:31–36. doi:10.1016/0531-5565(84)90029-9

    PubMed  Article  CAS  Google Scholar 

  • Moore G, Knoblaugh S, Gollahon K, Rabinovitch P, Ladiges W (2008) Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet. Mech Ageing Dev 129:201–206. doi:10.1016/j.mad.2007.12.009

    PubMed  Article  CAS  Google Scholar 

  • Muftuoğlu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA (2008) The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet 124:369–377. doi:10.1007/s00439-008-0562-0

    PubMed  Article  CAS  Google Scholar 

  • Mukhopadhyay SS, Leung KS, Hicks MJ, Hastings PJ, Youssoufian H, Plon SE (2006) Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia. J Cell Biol 175:225–235. doi:10.1083/jcb.200607061

    PubMed  Article  CAS  Google Scholar 

  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13. doi:10.1042/BJ20081386

    PubMed  Article  CAS  Google Scholar 

  • Musicco C, Capelli V, Pesce V, Timperio AM, Calvani M, Mosconi L, Zolla L, Cantatore P, Gadaleta MN (2009) Accumulation of overoxidized peroxiredoxin III in aged rat liver mitochondria. Biochim Biophys Acta 1787:890–896. doi:10.1016/j.bbabio.2009.03.002

    PubMed  Article  CAS  Google Scholar 

  • Navarro A, Gómez C, Sánchez-Pino MJ, González H, Bández MJ, Boveris AD, Boveris A (2005) Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice. Am J Physiol Regul Integr Comp Physiol 289:R1392–R1399. doi:10.1152/ajpregu.00834.2004

    PubMed  CAS  Google Scholar 

  • Neveling K, Bechtold A, Hoehn H (2007) Genetic instability syndromes with progeroid features. Z Gerontol Geriatr 40:339–348. doi:10.1007/s00391-007-0483-x

    PubMed  Article  CAS  Google Scholar 

  • Orr WC, Sohal RS (1994) Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263:1128–1130. doi:10.1126/science.8108730

    PubMed  Article  CAS  Google Scholar 

  • Pagano G, Degan P, D’Ischia M, Kelly FJ, Pallardo FV, Zatterale A, Anak SS, Akisik EE, Beneduce G, Calzone R, De Nicola E, Dunster C, Lloret A, Manini P, Nobili B, Saviano A, Vuttariello E, Warnau M (2004) Gender- and age-related distinctions for the in vivo prooxidant state in Fanconi anaemia patients. Carcinogenesis 25:1899–1909. doi:10.1093/carcin/bgh194

    PubMed  Article  CAS  Google Scholar 

  • Pagano G, Degan P, d’Ischia M, Kelly FJ, Nobili B, Pallardó FV, Zatterale A (2005a) Oxidative stress as a multiple effector in Fanconi anaemia clinical phenotype. Eur J Haematol 75:93–100. doi:10.1111/j.1600-0609.2005.00507

    PubMed  Article  CAS  Google Scholar 

  • Pagano G, Zatterale A, Degan P, d’Ischia M, Kelly FJ, Pallardó FV, Calzone R, Dunster C, Giudice A, Lloret A, Manini P, Masella R, Vuttariello E, Kılınç Y, Warnau M (2005b) In vivo prooxidant state in Werner syndrome patients. Free Radic Res 39:529–533. doi:10.1080/10715760500092683

    PubMed  Article  CAS  Google Scholar 

  • Pagano G, Zatterale A, Degan P, d’Ischia M, Kelly FJ, Pallardó FV, Kodama S (2005c) Multiple involvement of oxidative stress in Werner syndrome phenotype. Biogerontology 6:233–243. doi:10.1007/s10522-005-2624-1

    PubMed  Article  CAS  Google Scholar 

  • Palaniappan AR, Dai A (2007) Mitochondrial ageing and the beneficial role of alpha-lipoic acid. Neurochem Res 32:1552–1558. doi:10.1007/s11064-007-9355-4

    PubMed  Article  CAS  Google Scholar 

  • Pallardó FV, Degan P, d’Ischia M, Kelly FJ, Zatterale A, Calzone R, Castello G, Fernandez-Delgado R, Dunster C, Lloret A, Manini P, Pisanti MA, Vuttariello E, Pagano G (2006) Higher age-related prooxidant state in young Down syndrome patients indicates accelerated aging. Biogerontology 7:211–220. doi:10.1007/s10522-006-9002-5

    PubMed  Article  CAS  Google Scholar 

  • Paolini M, Pozzetti L, Pedulli GF, Marchesi E, Cantelli-Forti G (1999) The nature of prooxidant activity of vitamin C. Life Sci 64:273–278. doi:10.1016/S0024-3205(99)00167-8

    Google Scholar 

  • Patel KJ, Joenje H (2007) Fanconi anemia and DNA replication repair. DNA Repair 6:885–890. doi:10.1016/j.dnarep.2007.02.002

    PubMed  Article  CAS  Google Scholar 

  • Paulin-Levasseur M, Chen G, Larivière C (1998) The 2G2 antibody recognizes an acidic 110-kDa human mitochondrial protein. Histochem J 30:617–625. doi:10.1023/A:1003577609799

    PubMed  Article  CAS  Google Scholar 

  • Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168. doi:10.1016/j.cmet.2008.06.011

    PubMed  Article  CAS  Google Scholar 

  • Pereira S, Bourgeois P, Navarro C, Esteves-Vieira V, Cau P, De Sandre-Giovannoli A, Lévy N (2008) HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches. Mech Ageing Dev 129:449–459. doi:10.1016/j.mad.2008.04.003

    PubMed  Article  CAS  Google Scholar 

  • Pérez VI, Lew CM, Cortez LA, Webb CR, Rodriguez M, Liu Y, Qi W, Li Y, Chaudhuri A, Van Remmen H, Richardson A, Ikeno Y (2008) Thioredoxin 2 haploinsufficiency in mice results in impaired mitochondrial function and increased oxidative stress. Free Radic Biol Med 44:882–892. doi:10.1016/j.freeradbiomed.2007.11.018

    PubMed  Article  CAS  Google Scholar 

  • Perlman S, Becker-Catania S, Gatti RA (2003) Ataxia-telangiectasia: diagnosis and treatment. Semin Pediatr Neurol 10:173–182. doi:10.1016/S1071-9091(03)00026-3

    PubMed  Article  Google Scholar 

  • Pesce V, Fracasso F, Cassano P, Lezza AMS, Cantatore P, Gadaleta MN (2010) Acetyl-l-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating PGC-1alpha-dependent mitochondrial biogenesis. Rejuvenation Res. doi:10.1089/rej.2009.0955

  • Petrosillo G, Matera M, Casanova G, Ruggiero FM, Paradies G (2008) Mitochondrial dysfunction in rat brain with aging: involvement of complex I, reactive oxygen species and cardiolipin. Neurochem Int 53:126–131. doi:10.1016/j.neuint.2008.07.001

    PubMed  Article  CAS  Google Scholar 

  • Petrosillo G, Matera M, Moro N, Ruggiero FM, Paradies G (2009) Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin. Free Radic Biol Med 46:88–94. doi:10.1016/j.freeradbiomed.2008.09.031

    PubMed  Article  CAS  Google Scholar 

  • Plecitá-Hlavatá L, Jezek J, Jezek P (2009) Pro-oxidant mitochondrial matrix-targeted ubiquinone MitoQ10 acts as anti-oxidant at retarded electron transport or proton pumping within complex I. Int J Biochem Cell Biol 41:1697–1707. doi:10.1016/j.biocel.2009.02.015

    PubMed  Article  CAS  Google Scholar 

  • Prince J, Jia S, Båve U, Annerén G, Oreland L (1994) Mitochondrial enzyme deficiencies in Down’s syndrome. J Neural Transm Park Dis Dement Sect 8:171–181 PMID: 7748461

    PubMed  Article  CAS  Google Scholar 

  • Reddy PH (2009) Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer’s disease. CNS Spectr 14(8 Suppl 7):8–13 PMID: 19890241

    PubMed  Google Scholar 

  • Reliene R, Schiestl RH (2006) Antioxidant N-acetyl cysteine reduces incidence and multiplicity of lymphoma in Atm deficient mice. DNA Repair (Amst) 5:852–859. doi:10.1016/j.dnarep.2006.05.003

    Article  CAS  Google Scholar 

  • Roat E, Prada N, Ferraresi R, Giovenzana C, Nasi M, Troiano L, Pinti M, Nemes E, Lugli E, Biagioni O, Mariotti M, Ciacci L, Consolo U, Balli F, Cossarizza A (2007) Mitochondrial alterations and tendency to apoptosis in peripheral blood cells from children with Down syndrome. FEBS Lett 581:521–525. doi:10.1016/j.febslet.2006.12.058

    PubMed  Article  CAS  Google Scholar 

  • Robb EL, Page MM, Stuart JA (2009) Mitochondria, cellular stress resistance, somatic cell depletion and lifespan. Curr Aging Sci 2:12–27. doi:10.2174/1874609810902010012

    PubMed  Article  CAS  Google Scholar 

  • Rodriguez MC, Macdonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA (2007) Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35:235–242. doi:10.1002/mus.20688

    PubMed  Article  CAS  Google Scholar 

  • Rosca MG, Lemieux H, Hoppel CL (2009) Mitochondria in the elderly: is acetylcarnitine a rejuvenator? Adv Drug Deliv Rev 61:1332–1342. doi:10.1016/j.addr.2009.06.009

    PubMed  Article  CAS  Google Scholar 

  • Rousset S, Nocentini S, Rouillard D, Baroche C, Moustacchi E (2002) Mitochondrial alterations in Fanconi anemia fibroblasts following ultraviolet A or psoralen photoactivation. Photochem Photobiol 75:159–166. doi:10.1562/0031-8655(2002)0750159MAIFAF2.0.CO2

    PubMed  Article  CAS  Google Scholar 

  • Sastre J, Pallardó FV, Plá R, Pellín A, Juan G, O’Connor JE, Estrela JM, Miquel J, Viña J (1996) Aging of the liver: age-associated mitochondrial damage in intact hepatocytes. Hepatology 24:1199–1205. doi:10.1002/hep.510240536

    PubMed  Article  CAS  Google Scholar 

  • Savitha S, Panneerselvam C (2007) Mitigation of age-dependent oxidative damage to DNA in rat heart by carnitine and lipoic acid. Mech Ageing Dev 128:206–212. doi:10.1016/j.mad.2006.11.029

    PubMed  Article  CAS  Google Scholar 

  • Schuchmann S, Heinemann U (2000) Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: a model of Down’s syndrome. Free Radic Biol Med 28:235–250. doi:10.1016/S0891-5849(99)00226-9

    PubMed  Article  CAS  Google Scholar 

  • Sendur OF, Turan Y, Tastaban E, Serter M (2009) Antioxidant status in patients with osteoporosis: a controlled study. Joint Bone Spine 76:514–518. doi:10.1016/j.jbspin.2009.02.005

    PubMed  Article  CAS  Google Scholar 

  • Seo AY, Xu J, Servais S, Hofer T, Marzetti E, Wohlgemuth SE, Knutson MD, Chung HY, Leeuwenburgh C (2008) Mitochondrial iron accumulation with age and functional consequences. Aging Cell 7:706–716. doi:10.1111/j.1474-9726.2008.00418.x

    PubMed  Article  CAS  Google Scholar 

  • Sharma P, Rupar CA, Rip JW (1998) Consequences of aging on mitochondrial respiratory chain enzymes in cultured human fibroblasts treated with ascorbate. Gerontology 44:78–84. doi:10.1159/000021988

    PubMed  Article  CAS  Google Scholar 

  • Shen JC, Gray MD, Oshima J, Kamath-Loeb AS, Fry M, Loeb LA (1998) Werner syndrome protein. I. DNA helicase and DNA exonuclease reside on the same polypeptide. J Biol Chem 273:34139–34144. doi:10.1074/jbc.273.51.34139

    PubMed  Article  CAS  Google Scholar 

  • Stern N, Hochman A, Zemach N, Weizman N, Hammel I, Shiloh Y, Rotman G, Barzilai A (2002) Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. J Biol Chem 277:602–608. doi:10.1074/jbc.M106798200

    PubMed  Article  CAS  Google Scholar 

  • Strub A, Zufall N, Voos W (2003) The putative helical lid of the Hsp70 peptide-binding domain is required for efficient preprotein translocation into mitochondria. J Mol Biol 334:1087–1099. doi:10.1016/j.jmb.2003.10.023

    PubMed  Article  CAS  Google Scholar 

  • Takeuchi F, Harihara S, Nakamura K, Takubo K, Kanamori M, Goto M (2003) The mitochondrial DNA A3243G mutation in Werner’s syndrome. Exp Gerontol 38:339–342. doi:10.1016/S0531-5565(02)002090-7

    PubMed  Article  CAS  Google Scholar 

  • Tannenbaum A (1942) The genesis and growth of tumors. II. Effects of caloric restriction per se. Cancer Res 2:460–467

    CAS  Google Scholar 

  • Tarnopolsky MA (2008) The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Deliv Rev 60:1561–1567. doi:10.1016/j.addr.2008.05.001

    PubMed  Article  CAS  Google Scholar 

  • Traina G, Federighi G, Brunelli M, Scuri R (2009) Cytoprotective effect of acetyl-l-carnitine evidenced by analysis of gene expression in the rat brain. Mol Neurobiol 39:101–106. doi:10.1007/s12035-009-8056-1

    PubMed  Article  CAS  Google Scholar 

  • Tremblay CS, Huang FF, Habi O, Huard CC, Godin C, Levesque G, Carreau M (2008) HES1 is a novel interactor of the Fanconi anemia core complex. Blood 112:2062–2070. doi:10.1182/blood-2008-04-152710

    PubMed  Article  CAS  Google Scholar 

  • Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J, Jacobs HT, Larsson N-G (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–423. doi:10.1038/nature02517

    PubMed  Article  CAS  Google Scholar 

  • Turaga RV, Paquet ER, Sild M, Vignard J, Garand C, Johnson FB, Masson JY, Lebel M (2009) The Werner syndrome protein affects the expression of genes involved in adipogenesis and inflammation in addition to cell cycle and DNA damage responses. Cell Cycle 8:2080–2092 PMID: 19502800

    PubMed  CAS  Google Scholar 

  • Varma SD, Hegde KR (2007) Susceptibility of the ocular lens to nitric oxide: implications in cataractogenesis. J Ocul Pharmacol Ther 23:188–195. doi:10.1089/jop.2006.0124

    PubMed  Article  CAS  Google Scholar 

  • Vila M, Ramonet D, Perier C (2008) Mitochondrial alterations in Parkinson’s disease: new clues. J Neurochem 107:317–328. doi:10.1111/j.1471-4159.2008.05604

    PubMed  Article  CAS  Google Scholar 

  • Van Raamsdonk JM, Hekimi S (2009) Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 5:e1000361. doi:10.1371/journal.pgen.1000361

  • von Kobbe C, Harrigan JA, May A, Opresko PL, Dawut L, Cheng WH, Bohr VA (2003) Central role for the Werner syndrome protein/poly(ADP-ribose) polymerase 1 complex in the poly(ADP-ribosyl)ation pathway after DNA damage. Mol Cell Biol 23:8601–8613. doi:10.1128/MCB.23.23.8601-8613.2003

    Article  CAS  Google Scholar 

  • von Kobbe C, May A, Grandori C, Bohr VA (2004) Werner syndrome cells escape hydrogen peroxide-induced cell proliferation arrest. FASEB J 18:1970–1972. doi:10.1096/fj.04-1895fje

    Google Scholar 

  • Wadhwa R, Yaguchi T, Hasan MK, Taira K, Kaul SC (2003) Mortalin-MPD (mevalonate pyrophosphate decarboxylase) interactions and their role in control of cellular proliferation. Biochem Biophys Res Commun 302:735–742. doi:10.1016/S0006-291X(03)00226-2

    PubMed  Article  CAS  Google Scholar 

  • Wadhwa R, Takano S, Taira K, Kaul SC (2004) Reduction in mortalin level by its antisense expression causes senescence-like growth arrest in human immortalized cells. J Gene Med 6:439–444. doi:10.1002/jgm.530

    PubMed  Article  CAS  Google Scholar 

  • Wang W (2007) Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8:735–748. doi:10.1038/nrg2159

    PubMed  Article  CAS  Google Scholar 

  • Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 28:9090–9103. doi:10.1523/JNEUROSCI.1357-09.2009

    Article  CAS  Google Scholar 

  • Wei YH, Wu SB, Ma YS, Lee HC (2009) Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J 32:113–132 PMID: 19403001

    PubMed  Google Scholar 

  • Young AJ, Lowe GM (2001) Antioxidant and prooxidant properties of carotenoids. Arch Biochem Biophys 385:20–27. doi:10.1006/abbi.2000.2149

    PubMed  Article  CAS  Google Scholar 

  • Yu C-E, Oshima J, Fu Y-H, Wijsman EM, Hisama F, Alish R, Matthews S, Nakura J, Miki T, Quais S, Martin GM, Mulligan J, Schellenberg GD (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262. doi:10.1126/science.272.5259.258

    PubMed  Article  CAS  Google Scholar 

  • Zhang Q-S, Eaton L, Snyder ER, Houghtaling S, Mitchell JB, Finegold M, Van Waes C, Grompe M (2008) Tempol protects against oxidative damage and delays epithelial tumor onset in Fanconi anemia mice. Cancer Res 68:1601–1608. doi:10.1158/0008-5472.CAN-07-5186

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giovanni Pagano.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pallardó, F.V., Lloret, A., Lebel, M. et al. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. Biogerontology 11, 401–419 (2010). https://doi.org/10.1007/s10522-010-9269-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-010-9269-4

Keywords

  • Ataxia-Telangiectasia
  • Down Syndrome
  • Fanconi Anaemia
  • Werner Syndrome
  • Oxidative stress
  • Mitochondria
  • Reactive oxygen species