Evidence of mitochondrial dysfunction and impaired ros detoxifying machinery in fanconi anemia cells

ABSTRACT Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Majority of the 15 FA

genes and encoded proteins characterized so far are integrated into DNA repair pathways, however, other important functions cannot be excluded. FA cells are sensitive to oxidants, and

accumulation of oxidized proteins has been characterized for several FA subgroups. Clinical phenotypes of both FA and other closely related diseases suggest altered functions of

mitochondria, organelles responsible for cellular energetic metabolism, and also serving as an important producer and the most susceptible target from reactive oxidative species (ROS). In

this study, we have shown that elevated level of mitochondrial ROS in FA cells is in parallel with the decrease of mitochondrial membrane potential, the decrease of ATP production, impaired

oxygen uptake and pathological changes in the morphology of mitochondria. This is accompanied by inactivation of enzymes that are essential for the energy production (F1F0ATPase and

cytochrome C oxidase) and detoxification of ROS (superoxide dismutase, SOD1). In turn, overexpression of SOD1 could rescue oxygen consumption rate in FA-deficient cells. Importantly, the

depletion of mitochondria improved survival rate of mitomycin C treated FA cells suggesting that hypersensitivity of FA cells to chemotherapeutic drugs could be in part due to the

mitochondria-mediated oxidative stress. On the basis of our results, we propose that deficiency in FA genes lead to disabling mitochondrial ROS-scavenging machinery further affecting

mitochondrial functions and suppressing cell respiration. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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‘neuronal-like’ properties. _J Neurochem_ 1996; 67: 1897–1907. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We are grateful to Drs Itahana and Li Ying (Duke-NUS) for

technical help with OCR and Seahorse experiments. We also acknowledge Dr Alex Panov for helpful comments related to mitochondria isolation and Dr Casey’s lab, Duke-NUS sorting core facility

for technical help and sharing materials as well as Dr Surralles’lab for providing FA cell lines. We are indebted to Drs Giovani Pagano and Massimo Bogliolo for helpful critics upon writing

this manuscript. _Authors contribution:_ UK performed majority of experiments (except EM), WYJ and BHB performed EM experiments and analyzed the data, AL designed and performed the

experiments, analyzed and interpreted the data, drafted the manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cancer and Stem Cell Research Program, DUKE-NUS Graduate Medical School,

Singapore, Singapore U Kumari & A Lyakhovich * Department of Anatomy, Yong Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore W Ya Jun & B Huat

Bay Authors * U Kumari View author publications You can also search for this author inPubMed Google Scholar * W Ya Jun View author publications You can also search for this author inPubMed 

Google Scholar * B Huat Bay View author publications You can also search for this author inPubMed Google Scholar * A Lyakhovich View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to A Lyakhovich. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION

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THIS ARTICLE Kumari, U., Ya Jun, W., Huat Bay, B. _et al._ Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi Anemia cells. _Oncogene_ 33, 165–172

(2014). https://doi.org/10.1038/onc.2012.583 Download citation * Received: 04 May 2012 * Revised: 25 October 2012 * Accepted: 29 October 2012 * Published: 14 January 2013 * Issue Date: 09

January 2014 * DOI: https://doi.org/10.1038/onc.2012.583 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable

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mitochondria