Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure

Alexander G. Nickel, Albrecht Von Hardenberg, Mathias Hohl, Joachim R. Löffler, Michael Kohlhaas, Janne Becker, Jan Christian Reil, Andrey Kazakov, Julia Bonnekoh, Moritz Stadelmaier, Sarah Lena Puhl, Michael Wagner, Ivan Bogeski, Sonia Cortassa, Reinhard Kappl, Bastian Pasieka, Michael Lafontaine, C. Roy D. Lancaster, Thomas S. Blacker, Andrew R. HallMichael R. Duchen, Lars Kästner, Peter Lipp, Tanja Zeller, Christian Müller, Andreas Knopp, Ulrich Laufs, Michael Böhm, Markus Hoth, Christoph Maack

Research output: Contribution to journalArticle

Abstract

Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.

Original languageEnglish (US)
Pages (from-to)472-484
Number of pages13
JournalCell Metabolism
Volume22
Issue number3
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Nickel, A. G., Von Hardenberg, A., Hohl, M., Löffler, J. R., Kohlhaas, M., Becker, J., Reil, J. C., Kazakov, A., Bonnekoh, J., Stadelmaier, M., Puhl, S. L., Wagner, M., Bogeski, I., Cortassa, S., Kappl, R., Pasieka, B., Lafontaine, M., Lancaster, C. R. D., Blacker, T. S., ... Maack, C. (2015). Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metabolism, 22(3), 472-484. https://doi.org/10.1016/j.cmet.2015.07.008