Regulation of Liver Mitochondrial Function by Hydrogen Sulfide

Hydrogen sulfide (H2S) was conventionally viewed as a life-threatening environmental toxic gas. Studies in recent years have shown that with l-cysteine and/or homocysteine as the substrate, several enzymes catalyze H2S production in mammalian cells. Once produced, H2S participates in the regulation of numerous physiological and pathophysiological functions. The mitochondrion is where oxygen is used and ATP is produced. Also in this very same organelle, H2S is consumed and produced, and both processes are oxygen-dependent. Thus, mitochondrial functions are closely related to and are regulated by oxygen-dependent mitochondrial H2S metabolism. In liver mitochondria, hypoxia decreases H2S consumption via suppressed H2S oxidation and increases H2S production via the accumulation of H2S-generating enzymes. At physiologically relevant concentrations, H2S serves as an electron donor to promote ATP production in the mitochondrion. H2S also regulates mitochondrial cAMP homeostasis. Abnormal liver H2S metabolism leads to or deteriorates the development of fatty liver disease, diabetic liver dysfunction, ischemia-reperfusion injury, acute liver failure, portal hypertension, and cirrhosis. It is perceived that clinical interventions based on mitochondrial H2S metabolism and the cellular and molecular effects of H2S donors will find profound and significant applications in preventing and treating various liver diseases.