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

Maithily S. Nanadikar, Ana M. Vergel Leon, Jia Guo, Gijsbert J. Belle, Aline Jatho, Elvina S. Philip, Astrid F. Brandner, Rainer A. Böckmann, Runzhu Shi, Anke Zieseniss, Carla M. Siemssen, Katja Dettmer, Susanne Brodesser, Marlen Schmidtendorf, Jingyun Lee, Hanzhi Wu, Cristina M. Furdui, Sören Brandenburg, Joseph R. Burgoyne, Ivan Bogeski, Jan Riemer, Arpita Chowdhury, Peter Rehling, Tobias Bruegmann, Vsevolod V. Belousov and Dörthe M. Katschinski ()
Additional contact information
Maithily S. Nanadikar: University Medical Center Göttingen, Georg-August, University Göttingen
Ana M. Vergel Leon: University Medical Center Göttingen, Georg-August, University Göttingen
Jia Guo: University Medical Center Göttingen, Georg-August, University Göttingen
Gijsbert J. Belle: University Medical Center Göttingen, Georg-August, University Göttingen
Aline Jatho: University Medical Center Göttingen, Georg-August, University Göttingen
Elvina S. Philip: University Medical Center Göttingen, Georg-August, University Göttingen
Astrid F. Brandner: Friedrich-Alexander-Universität Erlangen-Nürnberg
Rainer A. Böckmann: Friedrich-Alexander-Universität Erlangen-Nürnberg
Runzhu Shi: University Medical Center Göttingen, Georg-August, University Göttingen
Anke Zieseniss: University Medical Center Göttingen, Georg-August, University Göttingen
Carla M. Siemssen: University Medical Center Göttingen, Georg-August, University Göttingen
Katja Dettmer: University of Regensburg
Susanne Brodesser: University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Marlen Schmidtendorf: University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Jingyun Lee: Wake Forest University School of Medicine
Hanzhi Wu: Wake Forest University School of Medicine
Cristina M. Furdui: Wake Forest University School of Medicine
Sören Brandenburg: University Medical Center Göttingen
Joseph R. Burgoyne: The British Heart Foundation Centre of Excellence
Ivan Bogeski: University Medical Center Göttingen, Georg-August, University Göttingen
Jan Riemer: University of Cologne
Arpita Chowdhury: University Medical Center Göttingen
Peter Rehling: University Medical Center Göttingen
Tobias Bruegmann: University Medical Center Göttingen, Georg-August, University Göttingen
Vsevolod V. Belousov: University Medical Center Göttingen, Georg-August, University Göttingen
Dörthe M. Katschinski: University Medical Center Göttingen, Georg-August, University Göttingen

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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 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 H2O2-dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes.

Date: 2023
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DOI: 10.1038/s41467-023-37744-x

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