Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure

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.

Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

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Redox Imaging Using Cardiac Myocyte-Specific Transgenic Biosensor Mice

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Application of Mouse Models to Research in Hearing and Balance

“…A recent essay (Kraev 2014) summarizes concerns over atypical stress responses in C57BL/6J mice potentially resulting from a null genotype for the Nnt gene, which encodes the enzyme nicotinamide nucleotide transhydrogenase. This mitochondrial enzyme increases the production of reactive oxygen species (ROS) under stressful conditions, so that its elimination appears protective (Nickel et al 2015). It was suggested that experiments related to stress responses be repeated in closely related C57BL/6N mice or other substrains that carry functioning Nnt alleles.…”