Yuuki Shimizu1, Rohini Polavarapu1, Kattri-Liis Eskla1, Chad K Nicholson1, Christopher A Koczor2, Rui Wang3, William Lewis2, Sruti Shiva4, David J Lefer5, John W Calvert6. 1. Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA. 2. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. 3. Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada. 4. Department of Pharmacology & Chemical Biology, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 5. Cardiovascular Center of Excellence, Department of Pharmacology, LSU Health Sciences Center, New Orleans, LA, USA. 6. Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: jcalver@emory.edu.
Abstract
BACKGROUND: Hydrogen sulfide (H2S) 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 H2S levels directly influenced cardiac mitochondrial content. RESULTS: Mice deficient in the H2S-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 H2S-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac H2S 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 H2S required AMP-activated protein kinase (AMPK) to induce PGC1α signaling and mitochondrial biogenesis. Finally, we found that restoring H2S 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.
BACKGROUND:Hydrogen sulfide (H2S) 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 H2S levels directly influenced cardiac mitochondrial content. RESULTS:Mice deficient in the H2S-producing enzyme, cystathionine γ-lyase (CSE KO) displayed diminished cardiac mitochondrial content when compared to wild-type hearts. In contrast, mice overexpressing CSE (CSETg) and mice supplemented with the orally active H2S-releasing prodrug, SG-1002, displayed enhanced cardiac mitochondrial content. Additional analysis revealed that cardiac H2S 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 H2S required AMP-activated protein kinase (AMPK) to induce PGC1α signaling and mitochondrial biogenesis. Finally, we found that restoring H2S 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.
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