Nicotinamide nucleotide transhydrogenase (Nnt) links the substrate requirement in brain mitochondria for hydrogen peroxide removal to the thioredoxin/peroxiredoxin (Trx/Prx) system [Metabolism]

April 10th, 2014 by Lopert, P., Patel, M.

Mitochondrial reactive oxygen species (ROS) are implicated in the etiology of multiple neurodegenerative diseases including Parkinsons disease (PD). Mitochondria are known to be net producers of ROS but recently we have shown that brain mitochondria can consume mitochondrial hydrogen peroxide (H2O2) in a respiration-dependent manner predominantly by the thioredoxin/peroxiredoxin (Trx/Prx) system. Here we sought to determine the mechanism linking mitochondrial respiration with H2O2 catabolism in brain mitochondria and dopaminergic cells. We hypothesized that nicotinamide nucleotide transhydrogenase (Nnt), which utilizes the proton gradient to generate NADPH from NADH and NADP+, provides the link between mitochondrial respiration and H2O2 detoxification through the Trx/Prx system. Pharmacological inhibition of Nnt in isolated brain mitochondria significantly decreased their ability to consume H2O2 in the presence, but not absence, of respiration substrates. Nnt inhibition in liver mitochondria, which do not require substrates to detoxify H2O2, had no effect. Pharmacological inhibition or lentiviral knockdown of Nnt in N27 dopaminergic cells a) decreased H2O2 catabolism b) decreased NADPH and increased NADP+ levels and c) decreased basal, spare and maximal mitochondrial oxygen consumption rates. Nnt deficient cells possessed higher levels of oxidized mitochondrial Prx which rendered them more susceptible to steady-state increases in H2O2 and cell death following exposure to subtoxic levels of paraquat. This data implicates Nnt as the critical link between the metabolic and H2O2 antioxidant function in brain mitochondria and suggests Nnt as a potential therapeutic target to improve the redox balance in conditions of oxidative stress associated with neurodegenerative diseases.
  • Posted in Journal of Biological Chemistry, Publications
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