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Divalent cation chelators citrate and EDTA unmask an intrinsic uncoupling pathway in isolated mitochondria

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Abstract

We demonstrate a suppression of ROS production and uncoupling of mitochondria by exogenous citrate in Mg2+ free medium. Exogenous citrate suppressed H2O2 emission and depolarized mitochondria. The depolarization was paralleled by the stimulation of respiration of mitochondria. The uncoupling action of citrate was independent of the presence of sodium, potassium, or chlorine ions, and it was not mediated by the changes in permeability of the inner mitochondrial membrane to solutes. The citrate transporter was not involved in the citrate effect. Inhibitory analysis data indicated that several well described mitochondria carriers and channels (ATPase, IMAC, ADP/ATP translocase, mPTP, mKATP) were not involved in citrate’s effect. Exogenous MgCl2 strongly inhibited citrate-induced depolarization. The uncoupling effect of citrate was demonstrated in rat brain, mouse brain, mouse liver, and human melanoma cells mitochondria. We interpreted the data as an evidence to the existence of a hitherto undescribed putative inner mitochondrial membrane channel that is regulated by extramitochondrial Mg2+ or other divalent cations.

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Acknowledgments

This work was supported in part by the National Institutes of Health/National Institute on Aging grant PO AG 14930 to A.A.Starkov, by Ministry of Education and Science of Russian Federation (state assessment 6.149.2014/К) to V.N.Popov, and by the MTA-SE Lendület Neurobiochemistry Research Division 95003 and OTKA K 100918 to C. Chinopoulos.

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Authors and Affiliations

  1. The Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY, 10065, USA

    Anatoly A. Starkov

  2. Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary

    Christos Chinopoulos, Csaba Konrad & Gergely Kiss

  3. Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Natalia N. Starkova

  4. School of Biological Sciences, Medical Biology Centre, Queens University Belfast, Belfast, UK

    Anna Stepanova

  5. Voronezh State University, Voronezh, Russia

    Vasily N. Popov

  6. MTA-SE Lendület Neurobiochemistry Research Group, Budapest, Hungary

    Christos Chinopoulos

Authors
  1. Anatoly A. Starkov
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  2. Christos Chinopoulos
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  3. Natalia N. Starkova
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  4. Csaba Konrad
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  5. Gergely Kiss
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  6. Anna Stepanova
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  7. Vasily N. Popov
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Correspondence to Anatoly A. Starkov.

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Starkov, A.A., Chinopoulos, C., Starkova, N.N. et al. Divalent cation chelators citrate and EDTA unmask an intrinsic uncoupling pathway in isolated mitochondria. J Bioenerg Biomembr 49, 3–11 (2017). https://doi.org/10.1007/s10863-016-9656-x

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  • DOI: https://doi.org/10.1007/s10863-016-9656-x

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