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Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi Anemia cells

Oncogene volume 33, pages 165–172 (2014)Cite this article

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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.

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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.

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Authors and Affiliations

  1. Cancer and Stem Cell Research Program, DUKE-NUS Graduate Medical School, Singapore, Singapore

    U Kumari & A Lyakhovich

  2. Department of Anatomy, Yong Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    W Ya Jun & B Huat Bay

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  1. U Kumari
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Correspondence to A Lyakhovich.

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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

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