Mitochondrial DNA variations and mitochondrial dysfunction in Fanconi anemia


Autoři: Avani Solanki aff001;  Aruna Rajendran aff002;  Sheila Mohan aff003;  Revathy Raj aff003;  Babu Rao Vundinti aff001
Působiště autorů: Department of Cytogenetics, National Institute of Immunohaematology, K.E.M. Hospital Campus, Parel, Mumbai, Maharashtra, India aff001;  Department of Hematology, Institute of Child Health and Hospital for Children, Egmore, Chennai, Tamil Nadu, India aff002;  Pediatric Haematology Department, Apollo Children’s Hospital, Chennai, Tamil Nadu, India aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227603

Souhrn

In-vitro studies with different Fanconi anemia (FA) cell lines and FANC gene silenced cell lines indicating involvement of mitochondria function in pathogenesis of FA have been reported. However, in-vivo studies have not been studied so far to understand the role of mitochondrial markers in pathogenesis of FA. We have carried out a systematic set of biomarker studies for elucidating involvement of mitochondrial dysfunction in disease pathogenesis for Indian FA patients. We report changes in the mtDNA number in 59% of FA patients studied, a high frequency of mtDNA variations (37.5% of non-synonymous variations and 62.5% synonymous variations) and downregulation of mtDNA complex-I and complex-III encoding genes of OXPHOS (p<0.05) as strong biomarkers for impairment of mitochondrial functions in FA. Deregulation of expression of mitophagy genes (ATG; p>0.05, Beclin-1; p>0.05, and MAP1-LC3, p<0.05) has also been observed, suggesting inability of FA cells to clear off impaired mitochondria. We hypothesize that accumulation of such impaired mitochondria in FA cells therefore may be the principal cause for bone marrow failure (BMF) and a plausible effect of inefficient clearance of impaired mitochondria in FA.

Klíčová slova:

Blood – Complement system – Gene expression – Immunoblotting – Mitochondria – Mitochondrial DNA – Mutation – Pathogenesis


Zdroje

1. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13. doi: 10.1042/BJ20081386 19061483

2. Mukhopadhyay SS, Leung KS, Hicks MJ, Hastings PJ, Youssoufi H, Plon SE. JCB: ARTICLE. 2006;175(2):225–35.

3. Kumari U, Jun WY, Bay BH, Lyakhovich A. Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi Anemia cells. Oncogene. 2013;(October 2012):1–8.

4. Lyakhovich A. Damaged mitochondria and overproduction of ROS in Fanconi anemia cells. Rare Dis. 2013;1(1):e24048.

5. Ravera S, Vaccaro D, Cuccarolo P, Columbaro M, Capanni C, Bartolucci M, et al. Biochimie Mitochondrial respiratory chain Complex I defects in Fanconi anemia complementation group A. Biochimie. 2013;95(10):1828–37. doi: 10.1016/j.biochi.2013.06.006 23791750

6. Sumpter R, Levine B. Emerging functions of the Fanconi anemia pathway at a glance. 2017;2657–62. doi: 10.1242/jcs.204909 28811338

7. Sumpter R, Sirasanagandla S, Fernández ÁF, Wei Y, Dong X, Franco L, et al. Fanconi Anemia Proteins Function in Mitophagy and Immunity. Cell. 2016;165(4):867–81. doi: 10.1016/j.cell.2016.04.006 27133164

8. Solanki A, Mohanty P, Shukla P, Rao A, Ghosh K, Vundinti BR. FANCA gene mutations with 8 novel molecular changes in Indian Fanconi anemia patients. PLoS One. 2016;11(1):1–15.

9. Malik AN, Shahni R, Rodriguez-de-Ledesma A, Laftah A, Cunningham P. Mitochondrial DNA as a non-invasive biomarker: Accurate quantification using real time quantitative PCR without co-amplification of pseudogenes and dilution bias. Biochem Biophys Res Commun. 2011;412(1):1–7. doi: 10.1016/j.bbrc.2011.06.067 21703239

10. Rieder MJ, Taylor SL, Tobe VO, Nickerson DA. Automating the identification of DNA variations using quality-based fluorescence re-sequencing: Analysis of the human mitochondrial genome. Nucleic Acids Res. 1998;26(4):967–73. doi: 10.1093/nar/26.4.967 9461455

11. Cotan D, Cordero MD, Garrido-Maraver J, Oropesa-Avila M, Rodriguez-Hernandez A, Gomez Izquierdo L, et al. Secondary coenzyme Q10 deficiency triggers mitochondria degradation by mitophagy in MELAS fibroblasts. FASEB J. 2011;25(8):2669–87. doi: 10.1096/fj.10-165340 21551238

12. Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A, et al. Association of complementation group and mutation type with clinical outcome in Fanconi anemia. Blood. 2000;96(13):4064–70. 11110674

13. Mamrak NE, Shimamura A, Howlett NG. Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev. 2017;31(3):93–9. doi: 10.1016/j.blre.2016.10.002 27760710

14. Mozhey OI, Zatolokin PA, Vasilenko MA, Litvinova LS, Kirienkova E V., Mazunin IO. Evaluating the number of mitochondrial DNA copies in leukocytes and adipocytes from metabolic syndrome patients: Pilot study. Mol Biol. 2014;48(4):590–3.

15. Song J, Oh JY, Sung YA, Pak YK, Park KS, Lee HK. Peripheral blood mitochondrial DNA content is related to insulin sensitivity in offspring of type 2 diabetic patients. Diabetes Care. 2001;24(5):865–9. doi: 10.2337/diacare.24.5.865 11347745

16. Liu S-F, Kuo H-C, Tseng C-W, Huang H-T, Chen Y-C, Tseng C-C, et al. Leukocyte Mitochondrial DNA Copy Number Is Associated with Chronic Obstructive Pulmonary Disease. PLoS One. 2015;10(9):e0138716. doi: 10.1371/journal.pone.0138716 26394041

17. Thyagarajan B, Wang R, Nelson H, Barcelo H, Koh WP, Yuan JM. Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk. PLoS One. 2013;8(6).

18. Virbasius J V., Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: A potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A. 1994;91(4):1309–13. doi: 10.1073/pnas.91.4.1309 8108407

19. Vanniarajan A, Govindaraj P, Carlus SJ, Aruna M, Aruna P, Kumar A, et al. Mitochondrial DNA variations associated with recurrent pregnancy loss among Indian women. Mitochondrion. 2011;11(3):450–6. doi: 10.1016/j.mito.2011.01.002 21292039

20. Kabekkodu SP, Bhat S, Mascarenhas R, Mallya S, Bhat M, Pandey D, et al. Mitochondrial DNA variation analysis in cervical cancer. Mitochondrion. 2014;16:73–82. doi: 10.1016/j.mito.2013.07.001 23851045

21. Kazuno AA, Munakata K, Nagai T, Shimozono S, Tanaka M, Yoneda M, et al. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet. 2006;2(8):1167–77.

22. Linnartz B, Anglmayer R, Zanssen S. Comprehensive Scanning of Somatic Mitochondrial DNA Alterations in Acute Leukemia Developing from Myelodysplastic Syndromes. Cancer Res. 2004;64(6):1966–71. doi: 10.1158/0008-5472.can-03-2956 15026331

23. Reinecke F, Smeitink JAM, van der Westhuizen FH. OXPHOS gene expression and control in mitochondrial disorders. Biochim Biophys Acta—Mol Basis Dis. 2009;1792(12):1113–21.

24. Salehi MH, Kamalidehghan B, Houshmand M, Yong Meng G, Sadeghizadeh M, Aryani O, et al. Gene expression profiling of mitochondrial oxidative phosphorylation (OXPHOS) complex I in Friedreich ataxia (FRDA) patients. PLoS One. 2014;9(4).

25. Shyamsunder P, Esner M, Barvalia M, Wu YJ, Loja T, Boon HB, et al. Impaired mitophagy in Fanconi anemia is dependent on mitochondrial fission. Oncotarget. 2016;7(36):58065–74. doi: 10.18632/oncotarget.11161 27517150

26. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462(2):245–53. doi: 10.1016/j.abb.2007.03.034 17475204


Článek vyšel v časopise

PLOS One


2020 Číslo 1