Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium

Biochim Biophys Acta. Jun-Jul 2010;1797(6-7):1138-48. doi: 10.1016/j.bbabio.2010.04.002. Epub 2010 Apr 11.

Abstract

Although the functional role of nicotinamide nucleotide transhydrogenase (Nnt) remains to be fully elucidated, there is strong evidence that Nnt plays a critical part in mitochondrial metabolism by maintaining a high NADPH-dependent GSH/GSSG ratio, and thus the control of cellular oxidative stress. Using real-time PCR, spectrophotometric and western blotting techniques, we sought to determine the presence, abundance and activity level of Nnt in human heart tissues and to discern whether these are altered in chronic severe heart failure. Left ventricular levels of the NNT gene and protein expression did not differ significantly between the non-failing donor (NF) and heart failure (HF) group. Notably, compared to NF, Nnt activity rates in the HF group were 18% lower, which coincided with significantly higher levels of oxidized glutathione, lower glutathione reductase activity, lower NADPH and a lower GSH/GSSG ratio. In the failing human heart a partial loss of Nnt activity adversely impacts NADPH-dependent enzymes and the capacity to maintain membrane potential, thus contributing to a decline in bioenergetic capacity, redox regulation and antioxidant defense, exacerbating oxidative damage to cellular proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Citric Acid Cycle
  • Gene Expression
  • Glutathione / metabolism
  • Glutathione Disulfide / metabolism
  • Glutathione Reductase / metabolism
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Humans
  • In Vitro Techniques
  • Membrane Potential, Mitochondrial
  • Middle Aged
  • Mitochondria / metabolism*
  • Myocardium / metabolism*
  • NADP / metabolism
  • NADP Transhydrogenases / genetics
  • NADP Transhydrogenases / metabolism*
  • Oxidation-Reduction

Substances

  • NADP
  • NADP Transhydrogenases
  • Glutathione Reductase
  • Glutathione
  • Glutathione Disulfide