Independent studies have identified MDF in FA [1-6], an inherited bone marrow failure (BMF) syndrome associated with DNA damage and repair (DDR) pathways, along with susceptibility to non-lymphocytic leukemias and other malignancies, and other clinical complications such as diabetes and malformations [7,8]. FA represents a unique model disorder that raised general attention in the last decade since it was discovered that one of the encoded proteins by the FA subgroup D1 (FANCD1) was identical with the breast cancer-related BRCA2 gene [9]. The current state of knowledge on FA pathway relies on at least 16 genes corresponding to the FA genetic subgroups FA-A, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, -N, -O, -P and -Q [8,10]. When any of those genes is biallelically mutated, except for the X-linked FANCB, the FA disease occurs. The FA pathway is recognized to protect and regulate DNA from interstrand crosslinks [10-12]. Most of the mutations in the FA pathway inactivate a nuclear FA core complex, consisting of proteins FANCA, -B, -C, -E, -F, -G, -L, and -M and at least four FA-associated proteins, FAAP16, FAAP20, FAAP24, and FAAP100. The main known function of the FA core complex is to monoubiquitinate chromatin complex of two other FA proteins, FANCD2 and FANCI upon DNA damage [13-15]. Inactivation of the FA core complex does not allow monoubiquitination of FANCD2-FANCI, leading to a defect in downstream DNA repair signaling, consisting of FANCD1/BRCA2, FANCJ/BRIP1/BACH1, FANCN/PALB2, FANCO/SLX4, and FANCP/RAD51C. The ubiquitinated FANCD2 recruits ubiquitin zinc finger domain-containing DNA repair proteins such as FAN1, FANCP (SLX4), TLS polymerases eta and finally mediates DNA homologous recombination together with RAD51 and BRCA1 [16-24].

Another line of studies, dating back to 1980's, has provided consistent evidence for a role of OS in FA phenotype, such as excess oxygen sensitivity [25-27], in vitro and in vivo accumulation of oxidative DNA damage [28,29], and other anomalies of redox endpoints [30]. Most notably, direct implications of FANC proteins in redox pathways have been reported. The FANCC protein was found to be associated with redox-related activities, namely NADPH cytochrome P450 reductase [31,32] and GST [32]. The FANCG protein interacts with a P450 protein, cytochrome P450 2E1 (CYP2E1) [34], an activity also known to be involved in redox biotransformation of xenobiotics including, e.g., MMC [35,36]. The FANCA and FANCG proteins were found to respond to redox state in terms of physical structure related to their ability to form disulphide bonds in the FA protein complex. Thus, FANCA, FANCC and FANCG were found to interact with redox state, also accounting for excess MMC sensitivity [31-37]. A set of independent studies showed implications of BRCA1 (FANCD2) with OS. Dziaman et al. reported excess oxidative DNA damage in breast and ovary cancer patients with defective BRCA1 vs. cancer-free BRCA1 carriers and vs. control donors [38]. Another study by Li et al. showed functional interaction of FANCD2 and the forkhead transcription factor forkhead box O 3a (FOXO3a), which colocalized with FANCD2 foci in response to OS; the authors suggested that interacting FANCD2/FOXO3a contribute to cellular antioxidant defense [39,40].

Consistent with the links of FA phenotype – and of FA proteins - with OS, and given the well-established relationships between redox pathways and MDF, a set of independent studies revealed that mitochondria are actually involved in FA phenotype, from the observation that FANG localizes to mitochondria [2]. Major mitochondrial functions were found significantly altered in FA cells of genetic subtypes A, C, D2 and G, namely ATP production, mitochondrial membrane potential (ΔΘ), mitochondrial ultrastructure, defective mitochondrial peroxiredoxin-3, and oxygen consumption [1-3]; these malfunctions were not found in corrected FA cells. Another study, conducted on transcripts from bone marrow cells from FA patients vs. healthy donors, found that genes involved in mitochondrial bioenergetic pathways, i.e. Krebs cycle and electron transport chain were significantly down-regulated, approximately by 1.5- to 2-fold [4]. These findings, both arising from freshly drawn bone marrow cells and from lymphoblastoid cells or fibroblasts, point to an in vivo occurrence of MDF in FA patients, unconfined to FA cell cultures [1-4].

A possible scenario may be suggested for FA-associated MDF and OS: normal cell conditions undermine that mitochondria actively synthesize ATP (State 3) and the rate of electron transport is accelerated upon transferring ADP, phosphate and protons across the inner membrane. In that state almost 90% of oxygen is consumed by the respiratory chain and is reduced to water. One may assume that oxidative damage is accumulated in FA cells thus resulting in MDF and affecting both ATP production and cellular respiration. This state moves the majority of FA mitochondria toward semi-resting state (State 4), where ATP production is defective and the rate of oxygen consumption is low. All these events may result in mitochondrial abnormalities [1]. Our recent data, from six FA patients as reported in Appendix I, showed down-regulation of several mitochondrial genes in cells from FA patients, confirming an involvement of MDF in FA phenotype (Fig. 1). Among those genes, nicotinamide nucleotide transhydrogenase (NNT) may play a role in detoxifying ROS as it was found that NNT knockdown resulted in impaired redox potential and increased ROS levels [41]. NNT may control ROS level and cellular redox state by replenishment of GSH antioxidant systems and mitochondrial repair enzymes (thioredoxin, glutaredoxin, peroxiredoxins and phospholipid hydroperoxidase) and contribute to maintainence of the mitochondrial membrane potential through generation of a proton gradient [42,43].

Downregulation of mitochondrial genes in FA patients

Figure 1. Downregulation of mitochondrial genes in FA patients Total RNA isolated from peripheral blood of 6 Fanconi anemia patients from Andhra Mahila Sabha Hospital, Chennai, or from individuals with no symptoms of FA, was amplified using Express Art mRNA amplification kit micro version (Artus GmbH, Germany), labeled with Cy3 Post-Labeling Reactive Dye Pack (GE Healthcare UK limited, UK), fragmented and purified using Express Art Amino allyl mRNA amplification kit and YM10 columns (Millipore, USA). 10.0 mg of the labeled amplified RNA was used for hybridization with the Human 40K (A+B) OciChip array. Hybridization was performed using automated hybstation HS 4800. Hybridized chips were scanned using Affymetrix 428TM array scanner at three different PMT gains. Differentially expressed genes were filtered and the results represent the most downregulated mitochondrial genes. A threshold log fold change (LFC) of 3.0 was fixed to attain FDR of less than 0.05.

An involvement of OS and MDF in FA phenotype, far from being unique, is recognized for other disorders, including mitochondrial and other genetic diseases, as well as an extensive number of diseases pertaining to a broad range of medical disciplines, and involving mitochondrial damage to cells of, e.g., brain, heart, liver, blood, kidney, lung, and eye, as reviewed recently [5,6,44,45]. Table 1 shows a selection of cancer-prone and/or progeric genetic diseases, suggesting that they share clinical and biochemical features both involving defective DNA repair (DDR), and revealing a direct evidence of MDF/OS, including altered mitochondrial functions and/or ultrastructure, higher ROS levels and imbalance of cellular bioenergetics pathways. Interestingly, many of the mitochondrial-related diseases (MRD) show involvement of DDR pathways (either at mtDNA or at nuclear DNA level). Altogether, this allows us to suggest a simplified scheme (Fig. 2), where ROS accumulated in DDR may equally affect and damage mitochondria and - at the same time – defects in mitochondria may provoke accumulation of ROS followed by OS and DNA damage. In other terms, in spite of different origins, these two classes of diseases may contribute to common – or analogous - phenotypes.

Table 1. DDR-related diseases have elevated ROS and share phenotypes with mitochondria-related disorders (MRD)

DDR diseasePhenotypes common for MRDROS and mitochondrial involvementRef.
Ataxia-Telangiectasia (A-T or Louis–Bar syndrome)Impaired immunity, increased incidence of cancer, delayed onset or incomplete pubertal development, early menopause, slowed rate of growth, dysarthria, diabetes, premature changes in hair and skin;Intrinsic mtDNA repair defects; mitochondrial requirement for ATM activation by extranuclear OS;45-48
Bloom syndrome (BS or Bloom–Torre–Machacek syndrome)Deficiency in certain immunoglobulin classes, hypogonadism, premature cessation of menses, chronic lung problems, diabetes, and learning disabilities, mental retardation;Increased ROS production, mutations in energy metabolism gene PKM2, loss of mitochondrial membrane potential.49-51
de Barsy syndromeMusculoskeletal, neurological abnormalities, cataracts, short stature, dystonia, premature agingmutations in mitochondrial enzyme PYCR152
Cockayne syndromeGrowth failure, impaired development of the nervous system, photosensitivity, premature aging, hearing loss and eye abnormalitiesDeficiency in mitochondrial repair of 8-oxoguanine;
Cockayne syndrome (B) protein promotes mtDNA stability; high ROS level;		53-56
Cerebral palsy (CP)Disorders of the development of movement, epilepsy, apraxia, dysarthria, intellectual and learning disabilities, urinary incontinence, metabolic and cognitive dysregulationSensitivity to ROS,mitochondrial myopathies due to NADH dehydrogenase deficiency, generation of superoxide;57-59
Cornelia de Lange syndrome (CdLS)Growth and mental retardation, gastrointestinal disorders, brain abnormalities and hypertrophic cardiomyopathy;Mutated mitochondrial ribosomal protein MRPS22, OXPHOS complex I, III and IV deficiency;60
Fanconi anemia (FA)Growth retardation, diabetis, metabolic disorders, immunoresponse impairmentSome FA proteins are localized in mitochondria; high ROS and damaged mitochondria; accumulation of oxidized proteins in FA cells;1-6, 25-40,61,62
Friedreich's ataxiaLoss of coordination, vision and hearing impairment, diabetes, heart disordersDeficiency of a key encoded protein frataxin leads to mitochondrial iron overload;63
Li–Fraumeni syndromeSeveral kinds of cancer are involved;Increased oxidative metabolism64,65
Von Hippel-LindauHeadaches, vision problems, high blood pressure, hyperglycemiaVHL may contribute to tumorigenesis through mitochondria-based action, stimulates mitochondrial oxidative phosphorylation complex biogenesis, increased sensitivity of HIF-1α;63-68
Ligase IV (LIG4)Microcephaly, growth retardation, developmental delay, skin anomalies, immunodeficiency, diabetes;Participation in mitochondrial metabolism; the key encoded protein Tdp1 participates in the repair of mt DNA69-70
Nijmegen breakage syndrome (NBS)Microcephaly, short stature, immunodeficiency;Increased OS, defect in mitochondrial p53 accumulation;71
Retinoblastoma (Rb)Deterioration of vision, faltering growth or delayed development;Rb protein induces apoptosis directly at the mitochondria72,73
Spinocerebellar Ataxia (SCAE)EpilepsyMitochondria-mediated cell degeneration, MDF, OS74,75
Severe combined immunodeficiency (SCID)Defective antibody response, severe bacterial, viral, or fungal infections, lung diseaseMitochondrial adenylate kinase 2 malfunction76
Tuberous sclerosis complex (TSC)Cardiac rhabdomyomas, epilepsy, mental retardation and autism, brain lesions;Loss of Tsc1 is linked to MDF. Tdp1, a TSC gene, participates in the repair of mtDNA77,78
Xeroderma pigmentosum (XP)Diabetes mellitus, variable immune deficiency;Abnormal ultrastructural changes in mitochondria, OS and MDF;79,80
Wilms' tumor (nephroblastoma)High blood pressure, diabetes insipidusReduced aerobic energy metabolism81,82
Werner Syndrome (WS or progeria)Cataracts, diabetes (type 2), heart and arterial diseaseGeneration of mitochondrial ROS in the absence of WRN; contribution of the WRN mutation in mitochondrial DNA to diabetes mellitus83,84
Scheme illustrating possible involvement of ROS into phenotypes of DDR and MDR diseases

Figure 2. Scheme illustrating possible involvement of ROS into phenotypes of DDR and MDR diseases

It was a common stereotype that mitochondria were considered as organelles, only responsible for cellular energetic pathways. Conversely, only 3% of the genes necessary to make a mitochondrion are allocated for making ATP, whereas 97% are involved in the major metabolic pathways [85]. Mitochondria contain the rate-limiting enzymes for pyrimidine biosynthesis [85], heme synthesis [86], detoxification of ammonia in the urea cycle in the liver [87], cholesterol metabolism [88], neurotransmitter metabolism [89], free radical production and detoxification [90] and oxidative phosphorylation (OXPHOS) [91,92]. Not surprisingly, a mitochondrial basis to illness involves a number of neurologic and psychiatric disorders, malignancies, metabolic diseases, cardiovascular diseases, and autoimmune diseases [5,6,93-100].

Cancer predisposition in DDR diseases is a well-established fact and most of the DDR evolve various malignancies. Mitochondrial dysfunction has been also associated with a wide range of solid tumors, proposed to be central to the aging process, and found to be a common factor in the toxicity of a variety of xenobiotics [101]. An irreversible damage to OXPHOS leads to a shift in energy metabolism towards enhanced aerobic glycolysis in most cancers, thus mutations in mtDNA represent an early event during tumorigenesis. Due to the lack of introns, histones and limited repair mechanisms, mtDNA is more susceptible to mutations, including ROS-dependent ones. Mutations in mtDNA can contribute to the development of breast [102] and colorectal cancers [103], leukemia [104] and hepatocellular carcinoma [105]. There are many reasons to believe that ROS, acting both as mutagens and cellular mitogens, may play a role in tumor progression, thus suggesting a possible new avenue for the development of a treatment to suppress metastasis. In this regard, natural antioxidants should be considered for mitochondria-oriented FA therapy (mitochondrial nutrients, such as α-lipoic acid and coenzyme Q10) [6]. Interestingly, several compounds used in the treatment of FA patients, whose mechanisms of action in FA are largely unknown (ouabain, curcumin, androgen analogs) were also used in the treatment of MRD, e.g. heart disease (ouabain), or AD (curcumin) [106-108]. In MRD, these agents are known to inhibit Na(+)/K(+)-ATPase (ouabain), influence mitochondrial oxidation of cholesterol (oxandrolone, oxymetholone), prevent membrane permeability transition in mitochondria (thus reducing ROS by increasing glutathione) [106-112]. Therefore, it is highly suggestive that the effects of the above drugs in FA are linked to mitochondrial-related ROS. In addition to inactivating ROS by antioxidants, another strategy is to use artificial uncoupling agents that decrease proton gradient and then ROS production [113]. Unfortunately, therapeutic window(s) between efficacy and toxicity of such agents is too narrow. In order “to widen” the window between antioxidant and prooxidant concentrations, novel conjugates of plastoquinone and penetrating cations have been recently suggested [114]. Clinical studies focusing on novel ROS-scavenging compounds as well as agents preventing mitochondria from accumulation of ROS are warranted in the prospect of future therapy.

Supplementary Materials

Supplemental File

Conflicts of Interest

None

References

  • 1. 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;33:165-172. [PubMed] https://doi.org/10.1038/onc.2012.583
  • 2. Mukhopadhyay SS, Leung KS, Hicks MJ, Hastings PJ, Youssoufian H, Plon SE. Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia.J Cell Biol.2006;175:225-235. [PubMed] https://doi.org/10.1083/jcb.200607061
  • 3. Ravera S, Vaccaro D, Cuccarolo P, Columbaro M, Capanni C, Bartolucci M, Panfoli I, Morelli A, Dufour C, Cappelli E, Degan P. Mitochondrial respiratory chain Complex I defects in Fanconi anemia complementation group A.Biochimie.2013;95:1828-1837. [PubMed] https://doi.org/10.1016/j.biochi.2013.06.006
  • 4. Pagano G, Talamanca AA, Castello G, d'Ischia M, Pallardó FV, Petrović S, Porto B, Tiano L, Zatterale A. Bone marrow cell transcripts from Fanconi anaemia patients reveal in vivo alterations in mitochondrial, redox and DNA repair pathways.Eur J Haematol.2013;91:141-151. [PubMed] https://doi.org/10.1111/ejh.12131
  • 5. Pagano G, Talamanca AA, Castello G, d'Ischia M, Pallardó FV, Petrović S, Porto B, Tiano L, Zatterale A. 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. [PubMed] https://doi.org/10.1016/j.freeradbiomed.2013.01.015
  • 6. Pagano G, Talamanca AA, Castello G, Cordero MD, d'Ischia M, Gadaleta MN, Pallardó FV, Petrović S, Tiano L, Zatterale A. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: Toward a rational design of chemoprevention strategies by means of mitochondrial nutrients.Oxid Med Cell Longev.2014;doi: 10.1155/2014/541230 https://doi.org/10.1155/2014/541230 [PubMed]
  • 7. Garaycoechea JI and Patel KJ. Why does the bone marrow fail in Fanconi anemia?Blood.2014;123:26-34. [PubMed] https://doi.org/10.1182/blood-2013-09-427740
  • 8. Kee Y and D'Andrea AD. Molecular pathogenesis and clinical management of Fanconi anemia.J Clin Invest.2012;122:3799-3806. [PubMed] https://doi.org/10.1172/JCI58321
  • 9. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia.Science.2002;297:606-609. [PubMed] https://doi.org/10.1126/science.1073834
  • 10. Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, Trujillo JP, Minguillón J, Ramírez MJ, Pujol R, Casado JA, Baños R, Rio P, et al. DNA-repair endonuclease XPF, cause Fanconi anemia.Am J Hum Genet.2013;92:800-806. [PubMed] https://doi.org/10.1016/j.ajhg.2013.04.002
  • 11. Kee Y and D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability.Genes Dev.2010;24:1680-1694. [PubMed] https://doi.org/10.1101/gad.1955310
  • 12. Kennedy RD and D'Andrea AD. The Fanconi Anemia/BRCA pathway: new faces in the crowd.Genes Dev.2005;19:2925-2940. [PubMed] https://doi.org/10.1101/gad.1370505
  • 13. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge S J. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair.Cell.2007;129:289-301. [PubMed] https://doi.org/10.1016/j.cell.2007.03.009
  • 14. Polito D, Cukras S, Wang X, Spence P, Moreau L, D'Andrea AD, Kee Y. The Carboxy Terminus of FANCE recruits FANCD2 to the FA E3 ligase complex to promote the Fanconi Anemia DNA repair pathway.J Biol Chem.2014;doi: 10.1074/jbc.M113.533976 https://doi.org/10.1074/jbc.M113.533976 [PubMed]
  • 15. Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway.Nat Struct Mol Biol.2007;14:564-567. [PubMed] https://doi.org/10.1038/nsmb1252
  • 16. Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, et al. Identification of the Fanconi anemia complementation group I gene, FANCI.Cell Oncol.2007;29:211-218. [PubMed] https://doi.org/10.1155/2007/151968
  • 17. Joo W, Xu G, Persky NS, Smogorzewska A, Rudge DG, Buzovetsky O, Elledge SJ, Pavletich NP. Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.Science.2011;333:312-316. [PubMed] https://doi.org/10.1126/science.1205805
  • 18. Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51.Blood.2002;100:2414-2420. [PubMed] https://doi.org/10.1182/blood-2002-01-0278
  • 19. Kim H and D'Andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway.Genes Dev.2012;26:1393-1408. [PubMed] https://doi.org/10.1101/gad.195248.112
  • 20. Kratz K, Schopf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavo E, Sartori AA, Hengartner MO, Jiricny J. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.Cell.2010;142:77-88. [PubMed] https://doi.org/10.1016/j.cell.2010.06.022
  • 21. Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiacovo MP, Elledge S J. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair.Mol Cell.2010;39:36-47. [PubMed] https://doi.org/10.1016/j.molcel.2010.06.023
  • 22. Yamamoto KN, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, Jiricny J, Takeda S, Hirota K. Involvement of SLX4 in interstrand crosslink repair is regulated by the Fanconi anemia pathway.Proc Natl Acad Sci U S A.2011;108:6492-6496. [PubMed] https://doi.org/10.1073/pnas.1018487108
  • 23. Fu D, Dudimah FD, Zhang J, Pickering A, Paneerselvam J, Palrasu M, Wang H, Fei P. Recruitment of DNA polymerase eta by FANCD2 in the early response to DNA damage.Cell Cycle.2013;12:803-809. [PubMed] https://doi.org/10.4161/cc.23755
  • 24. Liu T, Ghosal G, Yuan J, Chen J, Huang J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.Science.2010;329:693-696. [PubMed] https://doi.org/10.1126/science.1192656
  • 25. Joenje H, Eriksson AW, Frants RR, Arwert F, Houwen B. Erythrocyte superoxide-dismutase deficiency in Fanconi's anaemia.Lancet.1978;1:204 [PubMed] https://doi.org/10.1016/s0140-6736(78)90632-3
  • 26. Joenje H, Arwert F, Eriksson AW, de Koning H, Oostra AB. Oxygen-dependence of chromosomal aberrations in Fanconi's anaemia.Nature.1981;290:142-143. [PubMed] https://doi.org/10.1038/290142a0
  • 27. Schindler D and Hoehn H. Fanconi anemia mutation causes cellular susceptibility to ambient oxygen.Am J Hum Genet.1988;43:429-435. [PubMed]
  • 28. Takeuchi T and Morimoto K. Increased formation of 8-hydroxydeoxyguanosine, an oxidative DNA damage, in lymphoblasts from Fanconi's anemia patients due to possible catalase deficiency.Carcinogenesis.1993;14:1115-11120. [PubMed] https://doi.org/10.1093/carcin/14.6.1115
  • 29. Degan P, Bonassi S, De Caterina M, Korkina LG, Pinto L, Scopacasa F, Zatterale A, Calzone R, Pagano G. In vivo accumulation of 8-hydroxy-2′-deoxyguanosine in DNA correlates with release of reactive oxygen species in Fanconi's anaemia families.Carcinogenesis.1995;16:735-741. [PubMed] https://doi.org/10.1093/carcin/16.4.735
  • 30. Pagano G, Degan P, d'Ischia M, Kelly FJ, Pallardó FV, Zatterale A, Anak SS, Akişık EE, Beneduce G, Calzone R, De Nicola E, Dunster C, Lloret A, et al. Gender- and age-related distinctions for the in vivo prooxidant state in Fanconi anaemia patients.Carcinogenesis.2004;25:1899-1909. [PubMed] https://doi.org/10.1093/carcin/bgh194
  • 31. Zhang X, Sejas DP, Qiu Y, Williams DA, Pang Q. Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence.J Cell Sci.2007;120:1572-1583. [PubMed] https://doi.org/10.1242/jcs.003152
  • 32. Kruyt FA, Hoshino T, Liu JM, Joseph P, Jaiswal AK, Youssoufian H. Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase.Blood.1998;2:3050-3056. [PubMed]
  • 33. Cumming RC, Lightfoot J, Beard K, Youssoufian H, O'Brien PJ, Buchwald M. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1.Nat Med.2001;7:814-820. [PubMed] https://doi.org/10.1038/89937
  • 34. Futaki M, Igarashi T, Watanabe S, Kajigaya S, Tatsuguchi A, Wang J, Liu JM. The FANCG Fanconi anemia protein interacts with CYP2E1: possible role in protection against oxidative DNA damage.Carcinogenesis.2002;23:67-72. [PubMed] https://doi.org/10.1093/carcin/23.1.67
  • 35. Pritsos CA and Sartorelli AC. Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics.Cancer Res.1986;46:3528-3532. [PubMed]
  • 36. Dusre L, Covey JM, Collins C, Sinha BK. DNA damage, cytotoxicity and free radical formation by mitomycin C in human cells.Chem Biol Interact.1989;71:63-78. [PubMed] https://doi.org/10.1016/0009-2797(89)90090-2
  • 37. Park SJ, Ciccone SL, Beck BD, Hwang B, Freie B, Clapp DW, Lee SH. Oxidative stress/damage induces multimerization and interaction of Fanconi anemia proteins.J Biol Chem.2004;279:30053-30059. [PubMed] https://doi.org/10.1074/jbc.M403527200
  • 38. Dziaman T, Huzarski T, Gackowski D, Rozalski R, Siomek A, Szpila A, Guz J, Lubinski J, Olinski R. Elevated level of 8-oxo-7,8-dihydro-2'-deoxyguanosine in leukocytes of BRCA1 mutation carriers compared to healthy controls.Int J Cancer.2009;125:2209-2213. [PubMed] https://doi.org/10.1002/ijc.24600
  • 39. Li J, Du W, Maynard S, Andreassen PR, Pang Q. Oxidative stress-specific interaction between FANCD2 and FOXO3a.Blood.2010;115:1545-1548. [PubMed] https://doi.org/10.1182/blood-2009-07-234385
  • 40. Li J, Sipple J, Maynard S, Mehta PA, Rose SR, Davies SM, Pang Q. Fanconi anemia links reactive oxygen species to insulin resistance and obesity.Antioxid Redox Signal.2012;17:1083-1098. [PubMed] https://doi.org/10.1089/ars.2011.4417
  • 41. Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nürnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, et al. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency.Nat Genet.2012;44:740-742. [PubMed] https://doi.org/10.1038/ng.2299
  • 42. Sheeran FL, Rydström J, Shakhparonov MI, Pestov NB, Pepe S. Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium.Biochim Biophys Acta.2010;1797:1138-1148. [PubMed] https://doi.org/10.1016/j.bbabio.2010.04.002
  • 43. Ronchi JA, Figueira TR, Ravagnani FG, Oliveira HC, Vercesi AE, Castilho RF. A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities.Free Radic Biol Med.2013;63:446-456. [PubMed] https://doi.org/10.1016/j.freeradbiomed.2013.05.049
  • 44. Pagano G, Talamanca AA, Castello G, Pallardó FV, Zatterale A, Degan P. Oxidative stress in Fanconi anaemia: from cells and molecules towards prospects in clinical management.Biol Chem.2012;393:11-21. [PubMed] https://doi.org/10.1515/BC-2011-227
  • 45. Pallardó FV, Lloret A, Lebel M, d'Ischia M, Cogger VC, Le Couteur DG, Gadaleta MN, Castello G, Pagano G. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome.Biogerontology.2010;11:401-419. [PubMed] https://doi.org/10.1007/s10522-010-9269-4
  • 46. Morita A, Tanimoto K, Murakami T, Morinaga T, Hosoi Y. Mitochondria are required for ATM activation by extranuclear oxidative stress in cultured human hepatoblastoma cell line Hep G2 cells.Biochem Biophys Res Commun.2014;443:1286-1290. [PubMed] https://doi.org/10.1016/j.bbrc.2013.12.139
  • 47. Sharma NK, Lebedeva M, Thomas T, Kovalenko OA, Stumpf JD, Shadel GS, Santos JH. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.DNA Repair (Amst).2014;13:22-31. [PubMed] https://doi.org/10.1016/j.dnarep.2013.11.002
  • 48. 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;21:42-48. [PubMed] https://doi.org/10.1038/mt.2012.203
  • 49. Popp HD and Bohlander SK. Genetic instability in inherited and sporadic leukemias.Genes Chromosomes Cancer.2010;49:1071-1081. [PubMed] https://doi.org/10.1002/gcc.20823
  • 50. Akhtar K, Gupta V, Koul A, Alam N, Bhat R, Bamezai RN. Differential behavior of missense mutations in the intersubunit contact domain of the human pyruvate kinase M2 isozyme.J Biol Chem.2009;284:11971-11981. [PubMed] https://doi.org/10.1074/jbc.M808761200
  • 51. Davalos AR and Campisi J. Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks.J Cell Biol.2003;162:1197-1209. [PubMed] https://doi.org/10.1083/jcb.200304016
  • 52. Dimopoulou A, Fischer B, Gardeitchik T, Schröter P, Kayserili H, Schlack C, Li Y, Brum JM, Barisic I, Castori M, Spaich C, Fletcher E, Mahayri Z, Bhat M, et al. Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.Mol Genet Metab.2013;110:352-361. [PubMed] https://doi.org/10.1016/j.ymgme.2013.08.009
  • 53. Stevnsner T, Nyaga S, de Souza-Pinto NC, van der Horst GT, Gorgels TG, Hogue BA, Thorslund T, Bohr VA. Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B.Oncogene.2002;21:8675-8682. [PubMed] https://doi.org/10.1038/sj.onc.1205994
  • 54. Aamann MD, Sorensen MM, Hvitby C, Berquist BR, Muftuoglu M, Tian J, de Souza-Pinto NC, Scheibye-Knudsen M, Wilson DM 3rd, Stevnsner T, Bohr VA. Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane.FASEB J.2010;24:2334-2346. [PubMed] https://doi.org/10.1096/fj.09-147991
  • 55. Scheibye-Knudsen M, Ramamoorthy M, Sykora P, Maynard S, Lin PC, Minor RK, Wilson DM 3rd, Cooper M, Spencer R, de Cabo R, Croteau DL, Bohr VA. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy.J Exp Med.2012;209:855-869. [PubMed] https://doi.org/10.1084/jem.20111721
  • 56. Andrade LN, Nathanson JL, Yeo GW, Menck CF, Muotri AR. Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome.Hum Mol Genet.2012;21:3825-3834. [PubMed] https://doi.org/10.1093/hmg/dds211
  • 57. Peterson MD, Gordon PM, Hurvitz EA, Burant CF. Secondary muscle pathology and metabolic dysregulation in adults with cerebral palsy.Am J Physiol Endocrinol Metab.2012;303:E1085-E1093. [PubMed] https://doi.org/10.1152/ajpendo.00338.2012
  • 58. Gerstner B, DeSilva TM, Genz K, Armstrong A, Brehmer F, Neve RL, Felderhoff-Mueser U, Volpe JJ, Rosenberg PA. Hyperoxia causes maturation-dependent cell death in the developing white matter.J Neurosci.2008;28:1236-1245. [PubMed] https://doi.org/10.1523/JNEUROSCI.3213-07.2008
  • 59. Tsao CY, Wright FS, Boesel CP, Luquette M. Partial NADH dehydrogenase defect presenting as spastic cerebral palsy.Brain Dev.1994;16:393-395. [PubMed] https://doi.org/10.1016/0387-7604(94)90127-9
  • 60. Smits P, Saada A, Wortmann SB, Heister AJ, Brink M, Pfundt R, Miller C, Haas D, Hantschmann R, Rodenburg RJ, Smeitink JA, van den Heuvel LP. Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy.Eur J Hum Genet.2011;19:394-399. [PubMed] https://doi.org/10.1038/ejhg.2010.214
  • 61. Baud O, Haynes RF, Wang H, Folkerth RD, Li J, Volpe JJ, Rosenberg PA. Developmental up-regulation of MnSOD in rat oligodendrocytes confers protection against oxidative injury.Eur J Neurosci.2004;20:29-40. [PubMed] https://doi.org/10.1111/j.0953-816X.2004.03451.x
  • 62. Lyakhovich A and Surrallés J. Constitutive activation of caspase-3 and Poly ADP ribose polymerase cleavage in fanconi anemia cells.Mol Cancer Res.2010;8:46-56. [PubMed] https://doi.org/10.1158/1541-7786.MCR-09-0373
  • 63. Evans-Galea MV, Lockhart PJ, Galea CA, Hannan AJ, Delatycki MB. Beyond loss of frataxin: the complex molecular pathology of Friedreich ataxia.Discov Med.2014;17:25-35. [PubMed]
  • 64. Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU, Strong LC, Talagala SL, Balaban RS, Kang JG, Hwang PM. Increased oxidative metabolism in the Li-Fraumeni syndrome.N Engl J Med.2013;368:1027-1032. [PubMed] https://doi.org/10.1056/NEJMoa1214091
  • 65. Zhou Q, Chen T, Ibe JC, Raj JU, Zhou G. Knockdown of von Hippel-Lindau protein decreases lung cancer cell proliferation and colonization.FEBS Lett.2012;586:1510-1515. [PubMed] https://doi.org/10.1016/j.febslet.2012.04.009
  • 66. Pantuck AJ, An J, Liu H, Rettig MB. NF-kappaB-dependent plasticity of the epithelial to mesenchymal transition induced by Von Hippel-Lindau inactivation in renal cell carcinomas.Cancer Res.2010;70:752-761. [PubMed] https://doi.org/10.1158/0008-5472.CAN-09-2211
  • 67. Hervouet E, Demont J, Pecina P, Vojtísková A, Houstek J, Simonnet H, Godinot C. A new role for the von Hippel-Lindau tumor suppressor protein: stimulation of mitochondrial oxidative phosphorylation complex biogenesis.Carcinogenesis.2005;26:531-539. [PubMed] https://doi.org/10.1093/carcin/bgi001
  • 68. Xiao H, Gu Z, Wang G, Zhao T. The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies.Int J Med Sci.2013;10:1412-1421. [PubMed] https://doi.org/10.7150/ijms.5630
  • 69. Li D, Suzuki H, Liu B, Morris J, Liu J, Okazaki T, Li Y, Chang P, Abbruzzese JL. DNA repair gene polymorphisms and risk of pancreatic cancer.Clin Cancer Res.2009;15:740-746. [PubMed] https://doi.org/10.1158/1078-0432.CCR-08-1607
  • 70. Arakawa H, Bednar T, Wang M, Paul K, Mladenov E, Bencsik-Theilen AA, Iliakis G. Functional redundancy between DNA ligases I and III in DNA replication in vertebrate cells.Nucleic Acids Res.2012;40:2599-2610. [PubMed] https://doi.org/10.1093/nar/gkr1024
  • 71. Turinetto V, Porcedda P, Minieri V, Orlando L, Lantelme E, Accomasso L, Amoroso A, De Marchi M, Zannini L, Delia D, Giachino C. A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells.DNA Repair (Amst).2010;9:1200-1208. [PubMed] https://doi.org/10.1016/j.dnarep.2010.09.003
  • 72. Witkiewicz AK, Cox DW, Rivadeneira D, Ertel AE, Fortina P, Schwartz GF, Knudsen ES. The retinoblastoma tumor suppressor pathway modulates the invasiveness of ErbB2-positive breast cancer.Oncogene.2013;doi:10.1038/onc.2013.367 https://doi.org/10.1038/onc.2013.367 [PubMed]
  • 73. Hilgendorf KI, Leshchiner ES, Nedelcu S, Maynard MA, Calo E, Ianari A, Walensky LD, Lees JA. The retinoblastoma protein induces apoptosis directly at the mitochondria.Genes Dev.2013;27:1003-1015. [PubMed] https://doi.org/10.1101/gad.211326.112
  • 74. Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration.J Neurosci.2009;29:9244-9254. [PubMed] https://doi.org/10.1523/JNEUROSCI.1532-09.2009
  • 75. Wang YC, Lee CM, Lee LC, Tung LC, Hsieh-Li HM, Lee-Chen GJ, Su MT. Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12.J Biol Chem.2011;286:SCA1221742-21754. [PubMed] https://doi.org/10.1074/jbc.M110.160697
  • 76. Burkart A, Shi X, Chouinard M, Corvera S. Adenylate kinase 2 links mitochondrial energy metabolism to the induction of the unfolded protein response.J Biol Chem.2011;286:4081-4089. [PubMed] https://doi.org/10.1074/jbc.M110.134106
  • 77. Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex.Proc Natl Acad Sci U S A.2011;108:E1070-E1079. [PubMed] https://doi.org/10.1073/pnas.1106454108
  • 78. Fam HK, Chowdhury MK, Walton C, Choi K, Boerkoel CF, Hendson G. Expression profile and mitochondrial colocalization of Tdp1 in peripheral human tissues.J Mol Histol.2013;44:481-494. [PubMed] https://doi.org/10.1007/s10735-013-9496-5
  • 79. Morrell D, Chase CL, Kupper LL, Swift M. Diabetes mellitus in ataxia-telangiectasia, Fanconi anemia, xeroderma pigmentosum, common variable immune deficiency, and severe combined immune deficiency families.Diabetes.1986;35:143-147. [PubMed] https://doi.org/10.2337/diab.35.2.143
  • 80. Plotnick H and Lupulescu A. Ultrastructural studies of xeroderma pigmentosum.J Am Acad Dermatol.1983;9:876-882. [PubMed] https://doi.org/10.1016/s0190-9622(83)70202-1
  • 81. Trushina E and McMurray CT. Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases.Neuroscience.2007;145:1233-1248. [PubMed] https://doi.org/10.1016/j.neuroscience.2006.10.056
  • 82. Feichtinger RG, Neureiter D, Royer-Pokora B, Mayr JA, Zimmermann FA, Jones N, Koegler C, Ratschek M, Sperl W, Kofler B. Heterogeneity of mitochondrial energy metabolism in classical triphasic Wilms' tumor.Front Biosci (Elite Ed).2011;3:187-193. [PubMed] https://doi.org/10.2741/e232
  • 83. Labbé A, Lafleur VN, Patten DA, Robitaille GA, Garand C, Lamalice L, Lebel M, Richard DE. The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity.Exp Cell Res.2012;318:1620-1632. [PubMed] https://doi.org/10.1016/j.yexcr.2012.04.010
  • 84. Takeuchi F, Harihara S, Nakamura K, Takubo K, Kanamori M, Goto M. The mitochondrial DNA A3243G mutation in Werner's syndrome.Exp Gerontol.2003;38:339-342. [PubMed] https://doi.org/10.1016/s0531-5565(02)002090-7
  • 85. Pagliarini DJ and Rutter J. Hallmarks of a new era in mitochondrial biochemistry.Genes Dev.2013;27:2615-2627. [PubMed] https://doi.org/10.1101/gad.229724.113
  • 86. Levi S and Rovida E. The role of iron in mitochondrial function.Biochim Biophys Acta.2009;1790:629-636. [PubMed] https://doi.org/10.1016/j.bbagen.2008.09.008
  • 87. Adeva MM, Souto G, Blanco N, Donapetry C. Ammonium metabolism in humans.Metabolism.2012;61:1495-1511. [PubMed] https://doi.org/10.1016/j.metabol.2012.07.007
  • 88. Martínez F. Regulation of mitochondrial cholesterol metabolism.Subcell Biochem.1997;28:205-234. [PubMed] https://doi.org/10.1007/978-1-4615-5901-6_8
  • 89. Alaynick WA. Nuclear receptors, mitochondria and lipid metabolism.Mitochondrion.2008;8:329-337. [PubMed] https://doi.org/10.1016/j.mito.2008.02.001
  • 90. Smaili SS, Ureshino RP, Rodrigues L, Rocha KK, Carvalho JT, Oseki KT, Bincoletto C, Lopes GS, Hirata H. The role of mitochondrial function in glutamate-dependent metabolism in neuronal cells.Curr Pharm Des.2011;17:3865-3877. [PubMed] https://doi.org/10.2174/138161211798357782
  • 91. Murray J, Oquendo CE, Willis JH, Marusich MF, Capaldi RA. Monitoring oxidative and nitrative modification of cellular proteins; a paradigm for identifying key disease related markers of oxidative stress.Adv Drug Deliv Rev.2008;60:1497-1503. [PubMed] https://doi.org/10.1016/j.addr.2008.05.003
  • 92. Bar-Yaacov D, Blumberg A, Mishmar D. Mitochondrial-nuclear co-evolution and its effects on OXPHOS activity and regulation.Biochim Biophys Acta.2012;1819:1107-1111. [PubMed] https://doi.org/10.1016/j.bbagrm.2011.10.008
  • 93. Dhillon VS and Fenech M. Mutations that affect mitochondrial functions and their association with neurodegenerative diseases.Mutat Res.2014;759C:1-13. https://doi.org/10.1016/j.mrrev.2013.09.001 [PubMed]
  • 94. Schapira AH. Mitochondrial diseases.Lancet.2012;379:1825-1834. [PubMed] https://doi.org/10.1016/S0140-6736(11)61305-6
  • 95. Shen GX. Mitochondrial dysfunction, oxidative stress and diabetic cardiovascular disorders.Cardiovasc Hematol Disord Drug Targets.2012;12:106-112. [PubMed] https://doi.org/10.2174/1871529x11202020106
  • 96. Thrush AB, Dent R, McPherson R, Harper ME. Implications of mitochondrial uncoupling in skeletal muscle in the development and treatment of obesity.FEBS J.2013;280:5015-5029. [PubMed] https://doi.org/10.1111/febs.12399
  • 97. Sims NR and Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke.Biochim Biophys Acta.2010;1802:80-91. [PubMed] https://doi.org/10.1016/j.bbadis.2009.09.003
  • 98. Moodley D, Mody G, Patel N, Chuturgoon AA. Mitochondrial depolarisation and oxidative stress in rheumatoid arthritis patients.Clin Biochem.2008;41:1396-1401. [PubMed] https://doi.org/10.1016/j.clinbiochem.2008.08.072
  • 99. Witte ME, Mahad DJ, Lassmann H, van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis.Trends Mol Med.2013;20:179-187. [PubMed] https://doi.org/10.1016/j.molmed.2013.11.007
  • 100. Perl A, Gergely P Jr, Banki K. Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus.Int Rev Immunol.2004;23:293-313. [PubMed] https://doi.org/10.1080/08830180490452576
  • 101. Boland ML, Chourasia AH, Macleod KF. Mitochondrial Dysfunction in Cancer.Front Oncol.2013;3:292 [PubMed] https://doi.org/10.3389/fonc.2013.00292
  • 102. Yadav N and Chandra D. Mitochondrial DNA mutations and breast tumorigenesis.Biochim Biophys Acta.2013;1836:336-344. [PubMed] https://doi.org/10.1016/j.bbcan.2013.10.002
  • 103. Dimberg J, Hong TT, Skarstedt M, Löfgren S, Zar N, Matussek A. Novel and differential accumulation of mitochondrial DNA deletions in Swedish and vietnamese patients with colorectal cancer.Anticancer Res.2014;34:147-152. [PubMed]
  • 104. Silkjaer T, Nørgaard JM, Aggerholm A, Ebbesen LH, Kjeldsen E, Hokland P, Nyvold CG. Characterization and prognostic significance of mitochondrial DNA variations in acute myeloid leukemia.Eur J Haematol.2013;90:385-396. [PubMed] https://doi.org/10.1111/ejh.12090
  • 105. Hsu CC, Lee HC, Wei YH. Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma.World J Gastroenterol.2013;19:8880-8886. [PubMed] https://doi.org/10.3748/wjg.v19.i47.8880
  • 106. Jun DW, Hwang M, Kim HJ, Hwang SK, Kim S, Lee CH. Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents.PLoS One.2013;8:e75905 [PubMed] https://doi.org/10.1371/journal.pone.0075905
  • 107. Giordano CR and Terlecky SR. Peroxisomes, cell senescence, and rates of aging.Biochim Biophys Acta.2012;1822:1358-1362. [PubMed] https://doi.org/10.1016/j.bbadis.2012.03.013
  • 108. Landais I, Hiddingh S, McCarroll M, Yang C, Sun A, Turker MS, Snyder JP, Hoatlin ME. Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors.Mol Cancer.2009;8:133 [PubMed] https://doi.org/10.1186/1476-4598-8-133
  • 109. Brondino N, Re S, Boldrini A, Cuccomarino A, Lanati N, Barale F, Politi P. Curcumin as a Therapeutic Agent in Dementia: A Mini Systematic Review of Human Studies.ScientificWorldJournal.2014;2014:174282 [PubMed] https://doi.org/10.1155/2014/174282
  • 110. Jat D, Parihar P, Kothari SC, Parihar MS. Curcumin reduces oxidative damage by increasing reduced glutathione and preventing membrane permeability transition in isolated brain mitochondria.Cell Mol Biol (Noisy-le-grand).2013;59 SupplOL1899-905. [PubMed]
  • 111. Rose SR, Kim MO, Korbee L, Wilson KA, Ris MD, Eyal O, Sherafat-Kazemzadeh R, Bollepalli S, Harris R, Jeng MR, Williams DA, Smith FO. Oxandrolone for the treatment of bone marrow failure in Fanconi anemia.Pediatr Blood Cancer.2014;61:11-19. [PubMed] https://doi.org/10.1002/pbc.24617
  • 112. Velazquez I and Alter BP. Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions.Am J Hematol.2004;77:257-267. [PubMed] https://doi.org/10.1002/ajh.20183
  • 113. Harper JA, Dickinson K, Brand MD. Mitochondrial uncoupling as a target for drug development for the treatment of obesity.Obes Rev.2001;2:255-265. [PubMed] https://doi.org/10.1046/j.1467-789x.2001.00043.x
  • 114. Severina II, Severin FF, Korshunova GA, Sumbatyan NV, Ilyasova TM, Simonyan RA, Rogov AG, Trendeleva TA, Zvyagilskaya RA, Dugina VB, Domnina LV, Fetisova EK, Lyamzaev KG, et al. In search of novel highly active mitochondria-targeted antioxidants: thymoquinone and its cationic derivatives.FEBS Lett.2013;587:2018-2024. [PubMed] https://doi.org/10.1016/j.febslet.2013.04.043