IDH3γ serves as a redox switch that regulates mitochondrial energy metabolism and contractility in the heart under oxidative stress

Redox signaling and cardiac function are tightly linked. Still, it is largely unknown which protein targets are affected by H2O2 in cardiomyocytes that underly the impaired inotropic effects in oxidative stress. Here, we combined a new chemogenetic mouse model (HyPer-DAO mice) and a redox proteomics approach to identify redox sensitive proteins. Using the HyPer-DAO mice, we prove that increased endogenous production of H2O2 in cardiomyocytes leads to a reversibly impaired cardiac contractility in vivo. We identified the γ-subunit of the TCA cycle enzyme isocitrate dehydrogenase (IDH)3 as a redox switch and link its modification to mitochondrial metabolism and glutathione synthesis. Microsecond molecular dynamics simulations combined with experiments using cysteine-gene-edited point mutated cells revealed that IDH3γ Cys148 and 284 are critically involved in H2O2-dependent regulation of IDH3 activity. The oxidative modification of IDH3γ regulates the competition between energy production by TCA cycle flux and cellular anti-oxidant defense by glutathione synthesis.