Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK

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.

Keywords: AMPK; Heart; Hydrogen sulfide; Mitochondria.