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

Nanadikar MS, Vergel Leon AM, Guo J, van Belle GJ, Jatho A, Philip ES, Brandner A, Böckmann R, Shi R, Zieseniss A, Siemssen CM, Dettmer K, Brodesser S, Schmidtendorf M, Lee J, Wu H, Furdui CM, Brandenburg S, Burgoyne JR, Bogeski I, Riemer J, Chowdhury A, Rehling P, Bruegmann T, Belousov VV, Katschinski DM (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 14

Article Number: 2123

Journal Issue: 1

DOI: 10.1038/s41467-023-37744-x

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.

Authors with CRIS profile

Astrid Brandner Giménez Professur für Computational Biology Rainer Böckmann Professur für Computational Biology

Additional Organisation(s)

FAU Profilzentrum Licht.Materie.Quantentechnologien (FAU LMQ)

Involved external institutions

Universitätsklinikum Göttingen DE Germany (DE) Universität Regensburg DE Germany (DE) Universität zu Köln DE Germany (DE) Wake Forest School of Medicine US United States (USA) (US) British Heart Foundation (BHF) GB United Kingdom (GB)

How to cite

APA:

Nanadikar, M.S., Vergel Leon, A.M., Guo, J., van Belle, G.J., Jatho, A., Philip, E.S.,... Katschinski, D.M. (2023). IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart. Nature Communications, 14(1). https://dx.doi.org/10.1038/s41467-023-37744-x

MLA:

Nanadikar, Maithily S., et al. "IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart." Nature Communications 14.1 (2023).

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