Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure

Cell Metab. 2015 Sep 1;22(3):472-84. doi: 10.1016/j.cmet.2015.07.008. Epub 2015 Aug 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cells, Cultured
  • Glutathione / metabolism
  • Heart Failure / metabolism*
  • Heart Failure / pathology
  • Mice, Inbred C57BL
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / pathology
  • NADP / metabolism*
  • NADP Transhydrogenases / metabolism*
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • NADP
  • Adenosine Triphosphate
  • NADP Transhydrogenases
  • Glutathione