IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart

Protein targets that are affected by ROS and underly impaired inotropic effects in the heart are largely unknown. Here, the authors identify the gamma-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function. Redox signaling and cardiac function are tightly linked. However, it is largely unknown which protein targets are affected by hydrogen peroxide (H2O2) in cardiomyocytes that underly impaired inotropic effects during oxidative stress. Here, we combine a chemogenetic mouse model (HyPer-DAO mice) and a redox-proteomics approach to identify redox sensitive proteins. Using the HyPer-DAO mice, we demonstrate that increased endogenous production of H2O2 in cardiomyocytes leads to a reversible impairment of cardiac contractility in vivo. Notably, we identify the gamma-subunit of the TCA cycle enzyme isocitrate dehydrogenase (IDH)3 as a redox switch, linking its modification to altered mitochondrial metabolism. Using microsecond molecular dynamics simulations and experiments using cysteine-gene-edited cells reveal that IDH3 gamma Cys148 and 284 are critically involved in the H2O2-dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes.

Automated summary

The authors identify the gamma-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function, providing new insights into the relationship between redox signaling and cardiac function. They demonstrate that increased endogenous production of H2O2 leads to reversible impairment of cardiac contractility and identify specific cysteine residues in IDH3 gamma as critical for H2O2-dependent regulation of IDH3 activity.