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

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Listed:
  • 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
    University of Oxford)

  • Rainer A. Böckmann

    (Friedrich-Alexander-Universität Erlangen-Nürnberg
    Erlangen National High-Performance Computing Center (NHR@FAU))

  • 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
    DZHK (German Center for Cardiovascular Research), Partner Site 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
    University of Göttingen
    Translational Neuroinflammation and Automated Microscopy
    Max Planck Institute for Multidisciplinary Sciences)

  • Tobias Bruegmann

    (University Medical Center Göttingen, Georg-August, University Göttingen
    DZHK (German Center for Cardiovascular Research), Partner Site Göttingen
    University of Göttingen)

  • Vsevolod V. Belousov

    (University Medical Center Göttingen, Georg-August, University Göttingen
    Federal Center of Brain Research and Neurotechnologies, Federal Medical Agency)

  • Dörthe M. Katschinski

    (University Medical Center Göttingen, Georg-August, University Göttingen
    DZHK (German Center for Cardiovascular Research), Partner Site Göttingen)

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.

Suggested Citation

  • 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 & , 2023. "IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37744-x
    DOI: 10.1038/s41467-023-37744-x
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    References listed on IDEAS

    as
    1. Benjamin Steinhorn & Andrea Sorrentino & Sachin Badole & Yulia Bogdanova & Vsevolod Belousov & Thomas Michel, 2018. "Chemogenetic generation of hydrogen peroxide in the heart induces severe cardiac dysfunction," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. Jiska Reest & Sergio Lilla & Liang Zheng & Sara Zanivan & Eyal Gottlieb, 2018. "Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    3. Edward T. Chouchani & Victoria R. Pell & Edoardo Gaude & Dunja Aksentijević & Stephanie Y. Sundier & Ellen L. Robb & Angela Logan & Sergiy M. Nadtochiy & Emily N. J. Ord & Anthony C. Smith & Filmon Ey, 2014. "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS," Nature, Nature, vol. 515(7527), pages 431-435, November.
    Full references (including those not matched with items on IDEAS)

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