MDH2 is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

ABSTRACT The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD + and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD + redox stress have not been elucidated. Our work demonstrates the crucial role played by MDH2 in orchestrating the electron fuelling of the RC. On one hand, MDH2 mediated oxaloacetate (OAA) production allows mitochondria to metabolize pyruvate and glutamate and to feed complex I with NADH, whereas on the other hand, OAA inhibits complex II. This regulatory mechanism synergistically increases RC’s NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA favouring the oxidation of malate produced by the MAS.