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

TY - JOUR

T1 - IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart

AU - Nanadikar, Maithily S

AU - Vergel Leon, Ana M

AU - Guo, Jia

AU - van Belle, Gijsbert J

AU - Jatho, Aline

AU - Philip, Elvina S

AU - Brandner, Astrid F

AU - Böckmann, Rainer A

AU - Shi, Runzhu

AU - Zieseniss, Anke

AU - Siemssen, Carla M

AU - Dettmer, Katja

AU - Brodesser, Susanne

AU - Schmidtendorf, Marlen

AU - Lee, Jingyun

AU - Wu, Hanzhi

AU - Furdui, Cristina M

AU - Brandenburg, Sören

AU - Burgoyne, Joseph R

AU - Bogeski, Ivan

AU - Riemer, Jan

AU - Chowdhury, Arpita

AU - Rehling, Peter

AU - Bruegmann, Tobias

AU - Belousov, Vsevolod V

AU - Katschinski, Dörthe M

N1 - Funding Information: This work was funded by the Deutsche Forschungsgemeinschaft (DFG) IRTG1816 and Ka 1269/13-1 to D.M.K., by Germany’s Excellence Strategy—EXC 2067/1-390729940 to P.R., T.B. and the DFG‐funded SFB1002 (project A06 to P.R., A09 to S.B. and A14 to T.B.). We thank Annette Hillemann and Katja Brechtel-Curth for their expert technical support. We acknowledge support by the Open Access Publication Funds of the Göttingen University. Publisher Copyright: © 2023, The Author(s).

PY - 2023/4/14

Y1 - 2023/4/14

N2 - 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.

AB - 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.

KW - Mice

KW - Animals

KW - Hydrogen Peroxide/metabolism

KW - Mitochondria/metabolism

KW - Oxidation-Reduction

KW - Energy Metabolism

KW - Myocytes, Cardiac/metabolism

KW - Oxidative Stress

UR - http://www.scopus.com/inward/record.url?scp=85152460304&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-37744-x

DO - 10.1038/s41467-023-37744-x

M3 - Article

C2 - 37055412

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2123

ER -