Mitochondrial H₂S Regulates BCAA Catabolism in Heart Failure

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Metabolic Disorders

Background:

• Hydrogen sulfide (H₂S) plays crucial roles in mitochondrial function, including oxidative phosphorylation and ATP synthesis.
• 3-mercaptopyruvate sulfurtransferase (3-MST) is a key mitochondrial enzyme responsible for H₂S production.
• The role of 3-MST in cardiovascular disease, particularly heart failure, remains incompletely understood.

Purpose of the Study:

• To investigate the impact of global 3-MST deficiency on pressure overload-induced heart failure.
• To elucidate the mechanisms underlying 3-MST's function in cardiovascular health and disease.

Main Methods:

• Assessed 3-MST protein expression in human heart failure samples.
• Utilized a 3-MST knockout mouse model subjected to transverse aortic constriction to induce heart failure.
• Evaluated cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis.
• Employed untargeted metabolomics to identify altered metabolic pathways.

Main Results:

• Reduced myocardial 3-MST expression was observed in human heart failure patients.
• 3-MST knockout mice showed increased myocardial branched-chain amino acid accumulation, impaired mitochondrial respiration, and reduced ATP synthesis.
• 3-MST deficiency exacerbated cardiac and vascular dysfunction and worsened exercise capacity following pressure overload.
• Therapeutic interventions, including restoring branched-chain amino acid catabolism and H₂S administration, ameliorated the negative effects of 3-MST deficiency.

Conclusions:

• Mitochondrial H₂S produced by 3-MST plays a vital role in regulating branched-chain amino acid catabolism.
• 3-MST-derived H₂S confers significant cardiovascular protection in the context of heart failure.
• Targeting 3-MST or its downstream pathways represents a potential therapeutic strategy for heart failure.