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Author Notes:

Correspondence: John W. Calvert, Ph.D., Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, 380 Northyards Boulevard, Suite B, Atlanta, GA 30313, Phone: 404-251-0663, Fax: 404-251-0701, jcalver@emory.edu

These authors contributed equally: YS and RP


Research Funding:

This work was funded by grants from the American Heart Association (15POST25610016 and 16GRNT31190016 to J.W.C) and the National Institutes of Health (NIH) (1R01DK115213-01 and 5R01HL098481-05 to J.W.C. and 1R01HL092141, 1R01HL093579, 1U24HL094373, and 1P20HL113452 to D.J.L.).

This work was also supported by funding from the Carlyle Fraser Heart Center of Emory University Hospital Midtown to J.W.C. and an operation grant from the Canadian Institutes of Health Research to R.W.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Cell Biology
  • Cardiovascular System & Cardiology
  • Hydrogen sulfide
  • Mitochondria
  • Heart
  • AMPK
  • H2S

Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK


Journal Title:

Journal of Molecular and Cellular Cardiology


Volume 116


, Pages 29-40

Type of Work:

Article | Post-print: After Peer Review


Background: Hydrogen sulfide (H 2 S) is an important regulator of mitochondrial bioenergetics, but its role in regulating mitochondrial biogenesis is not well understood. Using both genetic and pharmacological approaches, we sought to determine if H 2 S levels directly influenced cardiac mitochondrial content. Results: Mice deficient in the H 2 S-producing enzyme, cystathionine γ-lyase (CSE KO) displayed diminished cardiac mitochondrial content when compared to wild-type hearts. In contrast, mice overexpressing CSE (CSE Tg) and mice supplemented with the orally active H 2 S-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac H 2 S levels influenced the nuclear localization and transcriptional activity of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) with higher levels having a positive influence and lower levels having a negative influence. Studies aimed at evaluating the underlying mechanisms found that H 2 S required AMP-activated protein kinase (AMPK) to induce PGC1α signaling and mitochondrial biogenesis. Finally, we found that restoring H 2 S levels with SG-1002 in the setting of heart failure increased cardiac mitochondrial content, improved mitochondrial respiration, improved ATP production efficiency, and improved cardiac function. Conclusions: Together, these results suggest that hydrogen sulfide is an important regulator of cardiac mitochondrial content and establishes that exogenous hydrogen sulfide can induce mitochondrial biogenesis via an AMPK-PGC1α signaling cascade.

Copyright information:

© 2018 Elsevier Ltd

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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