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

• Published in: Nature communications Vol. 14; no. 1; p. 2123
• Main Authors: Nanadikar, Maithily S., Vergel Leon, Ana M., Guo, Jia, van Belle, Gijsbert J., Jatho, Aline, Philip, Elvina S., Brandner, Astrid F., Böckmann, Rainer A., Shi, Runzhu, Zieseniss, Anke, Siemssen, Carla M., Dettmer, Katja, Brodesser, Susanne, Schmidtendorf, Marlen, Lee, Jingyun, Wu, Hanzhi, Furdui, Cristina M., Brandenburg, Sören, Burgoyne, Joseph R., Bogeski, Ivan, Riemer, Jan, Chowdhury, Arpita, Rehling, Peter, Bruegmann, Tobias, Belousov, Vsevolod V., Katschinski, Dörthe M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/35; 59; 631/80/304; 692/4019/592/75/74; 82/58; Animals; Cardiomyocytes; Energy Metabolism; Genetic modification; Heart; Heart function; Humanities and Social Sciences; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Isocitrate dehydrogenase; Metabolism; Mice; Mitochondria; Mitochondria - metabolism; Molecular dynamics; multidisciplinary; Muscle contraction; Myocytes, Cardiac - metabolism; Oxidation-Reduction; Oxidative metabolism; Oxidative Stress; Proteins; Proteomics; Science; Science (multidisciplinary); Signaling; Tricarboxylic acid cycle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37744-x

Redox signaling and cardiac function are tightly linked. However, it is largely unknown which protein targets are affected by hydrogen peroxide (H 2 O 2 ) 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 H 2 O 2 in cardiomyocytes leads to a reversible impairment of cardiac contractility in vivo. Notably, we identify the γ-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 IDH3γ Cys148 and 284 are critically involved in the H 2 O 2 -dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes. Protein targets that are affected by ROS and underly impaired inotropic effects in the heart are largely unknown. Here, the authors identify the γ-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function.