SUMMARY
The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. In contrast to ADP, NADH metabolically produced in the cytosol is not transported across the inner mitochondrial membrane and must be indirectly transferred inside mitochondria through the malate-aspartate shuttle (MAS) to fuel RC with electrons. MAS is the major pathway maintaining cytosolic NADH/NAD+ redox balance in mammalian tissues such as liver and heart and its activity is crucial for cell metabolism, division and survival. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other RC complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organisation would favour NADH oxidation. Surprisingly, our bioenergetic characterization of liver and heart mitochondria demonstrates that the RC systematically favours electrons provided by complex II. However, mitochondrial malate dehydrogenase (MDH2) mediated metabolic regulation can rewire respiratory chain electrons flow from succinate toward NADH oxidation in response to increase MAS activity. Interestingly, this new regulatory mechanism synergistically increases RC’s NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favor oxidation of cytosolic malate. This discovery demonstrates that MAS does not only passively balance cytosolic and mitochondrial NADH but instead, in response to cytosolic redox stress, MAS actively rewires RC’s fuelling, inhibiting complex II to prioritize cytosolic NADH oxidation and increase complex I oxidative capacity.
HIGHLIGHTS
Heart and liver respiratory chains preferentially oxidize succinate.
The preferential succinate oxidation is independent of the relative abundance of complex I and II.
MDH2 mediated feedback inhibition of complex II can counteract the preferential succinate oxidation to increase NADH oxidative capacity.
The malate-aspartate shuttle inhibits mitochondrial conversion of succinate into malate to prioritize the mitochondrial oxidation of cytosolic malate.
Competing Interest Statement
The authors have declared no competing interest.