Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle

Here, we investigate whether the elevated mitochondrial H₂O₂ release in small mammals arises from a tradeoff between NAD-dependent enzymes, which synthesizes NADH to support high oxidative phosphorylation, and NADP-dependent enzymes, which generates NADPH to detoxify H₂O₂ within the matrix. We measured the activities of NAD- and NADP-dependent enzymes in skeletal muscle mitochondria from mammal species ranging from 4 g to 600 kg. The activities of the two most active NADPH-producing enzymes increased, whereas NAD-dependent enzyme activities declined with body mass. Therefore, small mammals prioritize NADH synthesis at the expense of NADPH, increasing the oxidative cost of mitochondrial metabolism.