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Journal of Pediatric Biochemistry 2016; 06(02): 79-87
DOI: 10.1055/s-0036-1593756
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Mitochondrial Dysfunction and Oxidative Stress in Pediatric Diseases

Federica Lotti
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Serafina Perrone
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Ursula Geronzi
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Elisa Guidoni
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Federica Carra
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Elisa Belvisi
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Francesco Bazzini
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Giuseppe Buonocore
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
Salvatore Grosso
1   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
,
on behalf of the “Gruppo di Studio di Biochimica Clinica Neonatale della Società Italiana di Neonatologia” › Author Affiliations
Further Information

Publication History

05 June 2016

23 June 2016

Publication Date:
21 October 2016 (online)

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Abstract

Oxidative stress is a distinctive sign in a long series of human diseases, including metabolic, neurologic, and cancer disorders. Several studies demonstrated that the toxic effects resulting from a redox imbalance take place even during infant age. Recent literature focused in particular on the role exerted by unpaired mitochondrial function in the pathogenesis of these diseases. Oxidative damage and mitochondrial dysfunction are cofactors in the pathogenesis of diabetes, as well as major contributors to its associated complications, primarily represented by cardiovascular disease. In epilepsy, mitochondrial failure is thought to be one of the possible mechanisms for seizure generation through a dysregulation in calcium homeostasis; moreover, the prolonged seizure-related neuronal excitation is able to trigger mitochondrial damage, proving the existence of interdependency between epileptic activity and mitochondrial dysfunction. Oxidative stress plays a pivotal role in carcinogenesis, and its intervention has been demonstrated in the pathogenesis of cancer-prone genetic diseases. The identification of specific molecular targets linked to altered mitochondrial function allows to select more rational and appropriate supportive treatments using antioxidants and mitochondrial nutrients as potential new therapeutic approaches.

Keywords

oxidative stress - diabetes mellitus - epilepsy - cancer - mitochondrial dysfunction - antioxidants
 

  • References

  • 1 Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med 1991; 91 (3C) (suppl 3C) 14S-22S
    PubMedGoogle Scholar
  • 2 Halliwell B. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence?. Lancet 1994; 344 (8924) 721-724
    CrossrefPubMedGoogle Scholar
  • 3 Brieger K, Schiavone S, Miller Jr FJ, Krause KH. Reactive oxygen species: from health to disease. Swiss Med Wkly 2012; 142: w13659
    PubMedGoogle Scholar
  • 4 Gutowski M, Kowalczyk S. A study of free radical chemistry: their role and pathophysiological significance. Acta Biochim Pol 2013; 60 (1) 1-16
    PubMedGoogle Scholar
  • 5 Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005; 39: 359-407
    CrossrefPubMedGoogle Scholar
  • 6 Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon) 2014; 42 (12) 698-702
    CrossrefPubMedGoogle Scholar
  • 7 Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 2010; 12 (4) 537-577
    CrossrefPubMedGoogle Scholar
  • 8 Wada J, Nakatsuka A. Mitochondrial dynamics and mitochondrial dysfunction in diabetes. Acta Med Okayama 2016; 70 (3) 151-158
    PubMedGoogle Scholar
  • 9 Livingstone SJ, Levin D, Looker HC , et al; Scottish Diabetes Research Network Epidemiology Group; Scottish Renal Registry. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA 2015; 313 (1) 37-44
    CrossrefPubMedGoogle Scholar
  • 10 Dalla Pozza R, Bechtold S, Bonfig W , et al. Age of onset of type 1 diabetes in children and carotid intima medial thickness. J Clin Endocrinol Metab 2007; 92 (6) 2053-2057
    CrossrefPubMedGoogle Scholar
  • 11 Scaramuzza AE, Redaelli F, Giani E , et al. Adolescents and young adults with type 1 diabetes display a high prevalence of endothelial dysfunction. Acta Paediatr 2015; 104 (2) 192-197
    CrossrefPubMedGoogle Scholar
  • 12 Järvisalo MJ, Jartti L, Näntö-Salonen K , et al. Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation 2001; 104 (24) 2943-2947
    CrossrefPubMedGoogle Scholar
  • 13 El Samahy MH, Matter RM, Youssef OI, Shams El Din El Telbany MA, Kamal NA. Relation between carotid intima media thickness and oxidative stress markers in type 1 diabetic children and adolescents. J Diabetes Metab Disord 2013; 12 (1) 50
    CrossrefPubMedGoogle Scholar
  • 14 Davì G, Ciabattoni G, Consoli A , et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 1999; 99 (2) 224-229
    CrossrefPubMedGoogle Scholar
  • 15 Hinokio Y, Suzuki S, Hirai M, Suzuki C, Suzuki M, Toyota T. Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy. Diabetologia 2002; 45 (6) 877-882
    CrossrefPubMedGoogle Scholar
  • 16 Sakurai K, Katoh M, Someno K, Fujimoto Y. Apoptosis and mitochondrial damage in INS-1 cells treated with alloxan. Biol Pharm Bull 2001; 24 (8) 876-882
    CrossrefPubMedGoogle Scholar
  • 17 Kubisch HM, Wang J, Bray TM, Phillips JP. Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress. Diabetes 1997; 46 (10) 1563-1566
    CrossrefPubMedGoogle Scholar
  • 18 Mysore TB, Shinkel TA, Collins J , et al. Overexpression of glutathione peroxidase with two isoforms of superoxide dismutase protects mouse islets from oxidative injury and improves islet graft function. Diabetes 2005; 54 (7) 2109-2116
    CrossrefPubMedGoogle Scholar
  • 19 Tran B, Oliver S, Rosa J, Galassetti P. Aspects of inflammation and oxidative stress in pediatric obesity and type 1 diabetes: an overview of ten years of studies. Exp Diabetes Res 2012; 2012: 683680
    PubMedGoogle Scholar
  • 20 Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med 2011; 50 (5) 567-575
    CrossrefPubMedGoogle Scholar
  • 21 Wu D, Gong CX, Meng X, Yang QL. Correlation between blood glucose fluctuations and activation of oxidative stress in type 1 diabetic children during the acute metabolic disturbance period. Chin Med J (Engl) 2013; 126 (21) 4019-4022
    PubMedGoogle Scholar
  • 22 Altıncık A, Tuğlu B, Demir K, Çatlı G, Abacı A, Böber E. Relationship between oxidative stress and blood glucose fluctuations evaluated with daily glucose monitoring in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2016; 29 (4) 435-439
    PubMedGoogle Scholar
  • 23 Meng X, Gong C, Cao B , et al. Glucose fluctuations in association with oxidative stress among children with T1DM: comparison of different phases. J Clin Endocrinol Metab 2015; 100 (5) 1828-1836
    CrossrefPubMedGoogle Scholar
  • 24 Rosa JS, Flores RL, Oliver SR, Pontello AM, Zaldivar FP, Galassetti PR. Sustained IL-1α, IL-4, and IL-6 elevations following correction of hyperglycemia in children with type 1 diabetes mellitus. Pediatr Diabetes 2008; 9 (1) 9-16
    PubMedGoogle Scholar
  • 25 Jakus V, Bauerova K, Michalkova D, Carsky J. Values of markers of early and advanced glycation and lipoxidation in serum proteins of children with diabetes mellitus. Bratisl Lek Listy (Tlacene Vyd) 2000; 101 (9) 484-489
    PubMedGoogle Scholar
  • 26 Chiavaroli V, Giannini C, De Marco S, Chiarelli F, Mohn A. Unbalanced oxidant-antioxidant status and its effects in pediatric diseases. Redox Rep 2011; 16 (3) 101-107
    CrossrefPubMedGoogle Scholar
  • 27 Ahmad FK, He Z, King GL. Molecular targets of diabetic cardiovascular complications. Curr Drug Targets 2005; 6 (4) 487-494
    CrossrefPubMedGoogle Scholar
  • 28 Srivastava SK, Ramana KV, Bhatnagar A. Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev 2005; 26 (3) 380-392
    CrossrefPubMedGoogle Scholar
  • 29 Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63 (4) 582-592
    CrossrefPubMedGoogle Scholar
  • 30 Sato T, Iwaki M, Shimogaito N, Wu X, Yamagishi S, Takeuchi M. TAGE (toxic AGEs) theory in diabetic complications. Curr Mol Med 2006; 6 (3) 351-358
    CrossrefPubMedGoogle Scholar
  • 31 Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414 (6865) 813-820
    CrossrefPubMedGoogle Scholar
  • 32 Salmonowicz B, Krzystek-Korpacka M, Noczyńska A. Trace elements, magnesium, and the efficacy of antioxidant systems in children with type 1 diabetes mellitus and in their siblings. Adv Clin Exp Med 2014; 23 (2) 259-268
    CrossrefPubMedGoogle Scholar
  • 33 Jain SK, Kannan K, Lim G. Ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. Free Radic Biol Med 1998; 25 (9) 1083-1088
    CrossrefPubMedGoogle Scholar
  • 34 Jain SK, McVie R. Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients. Diabetes 1999; 48 (9) 1850-1855
    CrossrefPubMedGoogle Scholar
  • 35 Pelletier A, Coderre L. Ketone bodies alter dinitrophenol-induced glucose uptake through AMPK inhibition and oxidative stress generation in adult cardiomyocytes. Am J Physiol Endocrinol Metab 2007; 292 (5) E1325-E1332
    CrossrefPubMedGoogle Scholar
  • 36 Papanas N, Ziegler D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother 2014; 15 (18) 2721-2731
    CrossrefPubMedGoogle Scholar
  • 37 Hegazy SK, Tolba OA, Mostafa TM, Eid MA, El-Afify DR. Alpha-lipoic acid improves subclinical left ventricular dysfunction in asymptomatic patients with type 1 diabetes. Rev Diabet Stud 2013; 10 (1) 58-67
    CrossrefPubMedGoogle Scholar
  • 38 Scaramuzza A, Giani E, Redaelli F , et al. Alpha-lipoic acid and antioxidant diet help to improve endothelial dysfunction in adolescents with type 1 diabetes: a pilot trial. J Diabetes Res 2015; 2015: 474561
    PubMedGoogle Scholar
  • 39 De Blasio MJ, Huynh K, Qin C , et al. Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling. Free Radic Biol Med 2015; 87: 137-147
    CrossrefPubMedGoogle Scholar
  • 40 Mortensen SA, Rosenfeldt F, Kumar A , et al; Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail 2014; 2 (6) 641-649
    CrossrefPubMedGoogle Scholar
  • 41 Brauner H, Lüthje P, Grünler J , et al. Markers of innate immune activity in patients with type 1 and type 2 diabetes mellitus and the effect of the anti-oxidant coenzyme Q10 on inflammatory activity. Clin Exp Immunol 2014; 177 (2) 478-482
    CrossrefPubMedGoogle Scholar
  • 42 Ngugi AK, Bottomley C, Kleinschmidt I , et al. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 2011; 52 (6) 1052-1057
    CrossrefPubMedGoogle Scholar
  • 43 McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001; 63 (6) 815-846
    CrossrefPubMedGoogle Scholar
  • 44 Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, Rodríguez-Martínez E, Gómez PY. Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid Med Cell Longev 2014; 2014: 293689
    CrossrefPubMedGoogle Scholar
  • 45 Puttachary S, Sharma S, Stark S, Thippeswamy T. Seizure-induced oxidative stress in temporal lobe epilepsy. BioMed Res Int 2015; 2015: 745613
    PubMedGoogle Scholar
  • 46 Cardenas-Rodriguez N, Huerta-Gertrudis B, Rivera-Espinosa L , et al. Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models. Int J Mol Sci 2013; 14 (1) 1455-1476
    CrossrefPubMedGoogle Scholar
  • 47 Mariani E, Polidori MC, Cherubini A, Mecocci P. Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 827 (1) 65-75
    CrossrefPubMedGoogle Scholar
  • 48 Jellinger KA. General aspects of neurodegeneration. J Neural Transm Suppl 2003; 65 (65) 101-144
    PubMedGoogle Scholar
  • 49 Shin EJ, Jeong JH, Chung YH , et al. Role of oxidative stress in epileptic seizures. Neurochem Int 2011; 59 (2) 122-137
    CrossrefPubMedGoogle Scholar
  • 50 Martinc B, Grabnar I, Vovk T. The role of reactive species in epileptogenesis and influence of antiepileptic drug therapy on oxidative stress. Curr Neuropharmacol 2012; 10 (4) 328-343
    CrossrefPubMedGoogle Scholar
  • 51 Candelario-Jalil E, Ajamieh HH, Sam S, Martínez G, León Fernández OS. Nimesulide limits kainate-induced oxidative damage in the rat hippocampus. Eur J Pharmacol 2000; 390 (3) 295-298
    CrossrefPubMedGoogle Scholar
  • 52 Patel M, Liang LP, Roberts II LJ. Enhanced hippocampal F2-isoprostane formation following kainate-induced seizures. J Neurochem 2001; 79 (5) 1065-1069
    PubMedGoogle Scholar
  • 53 Rola R, Swiader M, Czuczwar SJ. Electroconvulsions elevate the levels of lipid peroxidation products in mice. Pol J Pharmacol 2002; 54 (5) 521-524
    PubMedGoogle Scholar
  • 54 Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 2000; 101 (3) 563-570
    CrossrefPubMedGoogle Scholar
  • 55 Patel M. Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med 2004; 37 (12) 1951-1962
    CrossrefPubMedGoogle Scholar
  • 56 Liang LP, Patel M. Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(−/+) mice. Free Radic Biol Med 2004; 36 (5) 542-554
    CrossrefPubMedGoogle Scholar
  • 57 Yiş U, Seçkin E, Kurul SH, Kuralay F, Dirik E. Effects of epilepsy and valproic acid on oxidant status in children with idiopathic epilepsy. Epilepsy Res 2009; 84 (2−3) 232-237
    CrossrefPubMedGoogle Scholar
  • 58 Verrotti A, Scardapane A, Franzoni E, Manco R, Chiarelli F. Increased oxidative stress in epileptic children treated with valproic acid. Epilepsy Res 2008; 78 (2−3) 171-177
    CrossrefPubMedGoogle Scholar
  • 59 Michoulas A, Tong V, Teng XW, Chang TK, Abbott FS, Farrell K. Oxidative stress in children receiving valproic acid. J Pediatr 2006; 149 (5) 692-696
    CrossrefPubMedGoogle Scholar
  • 60 Grosso S, Longini M, Rodriguez A , et al. Oxidative stress in children affected by epileptic encephalopathies. J Neurol Sci 2011; 300 (1–2) 103-106
    CrossrefPubMedGoogle Scholar
  • 61 Morimoto M, Satomura S, Hashimoto T, Ito E, Kyotani S. Oxidative stress measurement and prediction of epileptic seizure in children and adults with severe motor and intellectual disabilities. J Clin Med Res 2016; 8 (6) 437-444
    CrossrefPubMedGoogle Scholar
  • 62 Kang HC, Lee YM, Kim HD. Mitochondrial disease and epilepsy. Brain Dev 2013; 35 (8) 757-761
    CrossrefPubMedGoogle Scholar
  • 63 Zsurka G, Baron M, Stewart JD , et al. Clonally expanded mitochondrial DNA mutations in epileptic individuals with mutated DNA polymerase γ. J Neuropathol Exp Neurol 2008; 67 (9) 857-866
    CrossrefPubMedGoogle Scholar
  • 64 Kunz WS, Kudin AP, Vielhaber S , et al. Mitochondrial complex I deficiency in the epileptic focus of patients with temporal lobe epilepsy. Ann Neurol 2000; 48 (5) 766-773
    CrossrefPubMedGoogle Scholar
  • 65 Zsurka G, Kunz WS. Mitochondrial dysfunction and seizures: the neuronal energy crisis. Lancet Neurol 2015; 14 (9) 956-966
    CrossrefPubMedGoogle Scholar
  • 66 Khurana DS, Valencia I, Goldenthal MJ, Legido A. Mitochondrial dysfunction in epilepsy. Semin Pediatr Neurol 2013; 20 (3) 176-187
    CrossrefPubMedGoogle Scholar
  • 67 Goldenthal MJ, Kuruvilla T, Damle S , et al. Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: comparison with studies in muscle biopsy. Mol Genet Metab 2012; 105 (3) 457-462
    CrossrefPubMedGoogle Scholar
  • 68 Deckers CL, Hekster YA, Keyser A, van Lier HJ, Meinardi H, Renier WO. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 2001; 42 (11) 1387-1394
    CrossrefPubMedGoogle Scholar
  • 69 Berger I, Segal I, Shmueli D, Saada A. The effect of antiepileptic drugs on mitochondrial activity: a pilot study. J Child Neurol 2010; 25 (5) 541-545
    CrossrefPubMedGoogle Scholar
  • 70 Martinc B, Grabnar I, Vovk T. Antioxidants as a preventive treatment for epileptic process: a review of the current status. Curr Neuropharmacol 2014; 12 (6) 527-550
    PubMedGoogle Scholar
  • 71 Ben-Menachem E, Kyllerman M, Marklund S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res 2000; 40 (1) 33-39
    CrossrefPubMedGoogle Scholar
  • 72 Goldberg-Stern H, Oren H, Peled N, Garty BZ. Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study. J Child Neurol 2012; 27 (12) 1524-1528
    CrossrefPubMedGoogle Scholar
  • 73 Paprocka J, Dec R, Jamroz E, Marszał E. Melatonin and childhood refractory epilepsy − a pilot study. Med Sci Monit 2010; 16 (9) CR389-CR396
    PubMedGoogle Scholar
  • 74 Ogunmekan AO, Hwang PA. A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children. Epilepsia 1989; 30 (1) 84-89
    CrossrefPubMedGoogle Scholar
  • 75 Raju GB, Behari M, Prasad K, Ahuja GK. Randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopherol (vitamin E) as add-on therapy in uncontrolled epilepsy. Epilepsia 1994; 35 (2) 368-372
    CrossrefPubMedGoogle Scholar
  • 76 Bough KJ, Wetherington J, Hassel B , et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 2006; 60 (2) 223-235
    CrossrefPubMedGoogle Scholar
  • 77 Gano LB, Patel M, Rho JM. Ketogenic diets, mitochondria, and neurological diseases. J Lipid Res 2014; 55 (11) 2211-2228
    Google Scholar
  • 78 Evans MD, Dizdaroglu M, Cooke MS. Oxidative DNA damage and disease: induction, repair and significance. Mutat Res 2004; 567 (1) 1-61
    CrossrefPubMedGoogle Scholar
  • 79 Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 2004; 266 (1–2) 37-56
    CrossrefPubMedGoogle Scholar
  • 80 Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160 (1) 1-40
    CrossrefPubMedGoogle Scholar
  • 81 Dayem AA, Choi HY, Kim JH, Cho SG. Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers (Basel) 2010; 2 (2) 859-884
    CrossrefPubMedGoogle Scholar
  • 82 Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak MA. Can chromosomal instability initiate tumorigenesis?. Semin Cancer Biol 2005; 15 (1) 43-49
    CrossrefPubMedGoogle Scholar
  • 83 Degtyareva NP, Chen L, Mieczkowski P, Petes TD, Doetsch PW. Chronic oxidative DNA damage due to DNA repair defects causes chromosomal instability in Saccharomyces cerevisiae. Mol Cell Biol 2008; 28 (17) 5432-5445
    CrossrefPubMedGoogle Scholar
  • 84 Cerutti PA, Trump BF. Inflammation and oxidative stress in carcinogenesis. Cancer Cells 1991; 3 (1) 1-7
    PubMedGoogle Scholar
  • 85 Ferguson LR. Chronic inflammation and mutagenesis. Mutat Res 2010; 690 (1–2) 3-11
    CrossrefPubMedGoogle Scholar
  • 86 Pagano G, Talamanca AA, Castello G , et al. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: toward mitochondria-targeted clinical strategies. Oxid Med Cell Longev 2014; 2014: 541230
    PubMedGoogle Scholar
  • 87 Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005; 120 (4) 483-495
    CrossrefPubMedGoogle Scholar
  • 88 Barrera G, Gentile F, Pizzimenti S , et al. Mitochondrial dysfunction in cancer and neurodegenerative diseases: spotlight on fatty acid oxidation and lipoperoxidation products. Antioxidants (Basel) 2016; 5 (1) E7 10.3390/antiox5010007
    CrossrefPubMedGoogle Scholar
  • 89 Pandey PR, Liu W, Xing F, Fukuda K, Watabe K. Anti-cancer drugs targeting fatty acid synthase (FAS). Recent Patents Anticancer Drug Discov 2012; 7 (2) 185-197
    CrossrefPubMedGoogle Scholar
  • 90 Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 2010; 35 (8) 427-433
    CrossrefPubMedGoogle Scholar
  • 91 Warburg O. On the origin of cancer cells. Science 1956; 123 (3191) 309-314
    CrossrefPubMedGoogle Scholar
  • 92 Pallardó FV, 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 2010; 11 (4) 401-419
    CrossrefPubMedGoogle Scholar
  • 93 Meyn MS. Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet 1999; 55 (5) 289-304
    CrossrefPubMedGoogle Scholar
  • 94 Reliene R, Schiestl RH. Experimental antioxidant therapy in ataxia telangiectasia. Clin Med Oncol 2008; 2: 431-436
    PubMedGoogle Scholar
  • 95 Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med 2000; 133 (10) 770-778
    CrossrefPubMedGoogle Scholar
  • 96 Ziv S, Brenner O, Amariglio N , et al. Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia. Hum Mol Genet 2005; 14 (19) 2929-2943
    CrossrefPubMedGoogle Scholar
  • 97 Ludwig LB, Valiati VH, Palazzo RP , et al. Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents. BioMed Res Int 2013; 2013: 762048
    PubMedGoogle Scholar
  • 98 Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003; 3 (3) 155-168
    CrossrefPubMedGoogle Scholar
  • 99 Lavin MF, Birrell G, Chen P, Kozlov S, Scott S, Gueven N. ATM signaling and genomic stability in response to DNA damage. Mutat Res 2005; 569 (1–2) 123-132
    CrossrefPubMedGoogle Scholar
  • 100 Stumm M, Neubauer S, Keindorff S, Wegner RD, Wieacker P, Sauer R. High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia telangiectasia and Nijmegen breakage syndrome. Cytogenet Cell Genet 2001; 92 (3–4) 186-191
    CrossrefPubMedGoogle Scholar
  • 101 Ditch S, Paull TT. The ATM protein kinase and cellular redox signaling: beyond the DNA damage response. Trends Biochem Sci 2012; 37 (1) 15-22
    CrossrefPubMedGoogle Scholar
  • 102 Ambrose M, Gatti RA. Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. Blood 2013; 121 (20) 4036-4045
    CrossrefPubMedGoogle Scholar
  • 103 Cosentino C, Grieco D, Costanzo V. ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J 2011; 30 (3) 546-555
    CrossrefPubMedGoogle Scholar
  • 104 Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet 2007; 16 (18) 2154-2164
    CrossrefPubMedGoogle Scholar
  • 105 Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res 2009; 668 (1–2) 4-10
    CrossrefPubMedGoogle Scholar
  • 106 Kim H, D'Andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 2012; 26 (13) 1393-1408
    CrossrefPubMedGoogle Scholar
  • 107 Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 2004; 23 (4) 1000-1004
    CrossrefPubMedGoogle Scholar
  • 108 Pagano G, Talamanca AA, Castello G , et al. From clinical description, to in vitro and animal studies, and backward to patients: oxidative stress and mitochondrial dysfunction in Fanconi anemia. Free Radic Biol Med 2013; 58: 118-125
    CrossrefPubMedGoogle Scholar
  • 109 Kumari U, Ya Jun W, Huat Bay B, Lyakhovich A. Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi anemia cells. Oncogene 2014; 33 (2) 165-172
    CrossrefPubMedGoogle Scholar
  • 110 Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet 2004; 5 (10) 725-738
    CrossrefPubMedGoogle Scholar
  • 111 Seewald L, Taub JW, Maloney KW, McCabe ER. Acute leukemias in children with Down syndrome. Mol Genet Metab 2012; 107 (1–2) 25-30
    CrossrefPubMedGoogle Scholar
  • 112 Lott IT. Antioxidants in Down syndrome. Biochim Biophys Acta 2012; 1822 (5) 657-663
    CrossrefPubMedGoogle Scholar
  • 113 Capone GT. Down syndrome: advances in molecular biology and the neurosciences. J Dev Behav Pediatr 2001; 22 (1) 40-59
    CrossrefPubMedGoogle Scholar
  • 114 Weksberg R, Nishikawa J, Caluseriu O , et al. Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 2001; 10 (26) 2989-3000
    CrossrefPubMedGoogle Scholar
  • 115 Rauen KA. HRAS and the Costello syndrome. Clin Genet 2007; 71 (2) 101-108
    CrossrefPubMedGoogle Scholar
  • 116 Yang D, Wang MT, Tang Y , et al. Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L). Cancer Biol Ther 2010; 9 (2) 122-133
    CrossrefPubMedGoogle Scholar
  • 117 Kleefstra T, Wortmann SB, Rodenburg RJ , et al. Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway. Eur J Hum Genet 2011; 19 (2) 138-144
    CrossrefPubMedGoogle Scholar
  • 118 Anichini C, Lotti F, Pietrini A , et al. Antioxidant effects of potassium ascorbate with ribose in costello syndrome. Anticancer Res 2013; 33 (2) 691-695
    PubMedGoogle Scholar
  • 119 Anichini C, Lo Rizzo C, Longini M , et al. Beckwith–Wiedemann syndrome: potassium ascorbate with ribose therapy in a syndrome with high neoplastic risk. Anticancer Res 2011; 31 (11) 3973-3976
    PubMedGoogle Scholar
  • 120 D'Souza AD, Parish IA, Krause DS, Kaech SM, Shadel GS. Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia-telangiectasia. Mol Ther 2013; 21 (1) 42-48
    CrossrefPubMedGoogle Scholar
  • 121 Berni A, Meschini R, Filippi S, Palitti F, De Amicis A, Chessa L. L-carnitine enhances resistance to oxidative stress by reducing DNA damage in Ataxia telangiectasia cells. Mutat Res 2008; 650 (2) 165-174
    CrossrefPubMedGoogle Scholar
  • 122 Ponte F, Sousa R, Fernandes AP , et al. Improvement of genetic stability in lymphocytes from Fanconi anemia patients through the combined effect of α-lipoic acid and N-acetylcysteine. Orphanet J Rare Dis 2012; 7: 28
    CrossrefPubMedGoogle Scholar
  • 123 Tiano L, Carnevali P, Padella L , et al. Effect of Coenzyme Q10 in mitigating oxidative DNA damage in Down syndrome patients, a double blind randomized controlled trial. Neurobiol Aging 2011; 32 (11) 2103-2105
    CrossrefPubMedGoogle Scholar
  • 124 Tiano L, Padella L, Santoro L , et al. Prolonged coenzyme Q10 treatment in Down syndrome patients: effect on DNA oxidation. Neurobiol Aging 2012; 33 (3) 626.e1-626.e8
    CrossrefPubMedGoogle Scholar
  • 125 Pollard HB, Levine MA, Eidelman O, Pollard M. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo 2010; 24 (3) 249-255
    PubMedGoogle Scholar
  • 126 González MJ, Rosario-Pérez G, Guzmán AM , et al. Mitochondria, energy and cancer: the relationship with ascorbic acid. J Orthomol Med 2010; 25 (1) 29-38
    PubMedGoogle Scholar