Nanadikar, Maithily S. and Vergel Leon, Ana M. and Guo, Jia and van Belle, Gijsbert J. and Jatho, Aline and Philip, Elvina S. and Brandner, Astrid F. and Boeckmann, Rainer A. and Shi, Runzhu and Zieseniss, Anke and Siemssen, Carla M. and Dettmer, Katja and Brodesser, Susanne and Schmidtendorf, Marlen and Lee, Jingyun and Wu, Hanzhi and Furdui, Cristina M. and Brandenburg, Soren and Burgoyne, Joseph R. and Bogeski, Ivan and Riemer, Jan and Chowdhury, Arpita and Rehling, Peter and Bruegmann, Tobias and Belousov, Vsevolod V. and Katschinski, Dorthe M. (2023) IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart. NATURE COMMUNICATIONS, 14 (1): 2123. ISSN , 2041-1723
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ISOCITRATE DEHYDROGENASE; MASS-SPECTROMETRY; ROS; ACCUMULATION; MECHANISMS; INDICATOR; SUCCINATE; PROTEINS; DYNAMICS; TARGET; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Apr 2024 13:12 |
| Last Modified: | 18 Apr 2024 13:12 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60852 |
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