Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression

Area of Science:

• Biochemistry
• Cardiology
• Molecular Biology

Background:

• Serum lactate levels assess tissue hypoxia and outcomes in sepsis and septic shock.
• Lactate can undergo lactylation, a posttranslational modification.
• Sepsis frequently causes myocardial depression, necessitating investigation into lactate's role.

Purpose of the Study:

• To investigate the role of lactate in sepsis-induced myocardial depression.
• To identify specific proteins and mechanisms affected by lactylation in the septic heart.

Main Methods:

• Sepsis models in rats (LPS administration, CLP) and H9c2 cells.
• Proteomic analysis to identify lactylation sites.
• Site-directed mutagenesis of HADHA (trifunctional enzyme subunit alpha) at K166 and K728.
• Transcriptomic and metabolomic analyses.
• Assessment of mitochondrial function, ATP production, and cardiomyocyte contractility.

Main Results:

• Identified 1127 lysine lactylation sites, with 83 differentially modified.
• Confirmed lactylation at HADHA K166 and K728, influenced by lactate levels.
• Lactylation inhibited HADHA activity, disrupting mitochondrial function, ATP production, and energy metabolism.
• Reduced cardiomyocyte contraction force observed in vitro and in vivo.
• Sirtuin 1 and Sirtuin 3 were identified as regulators of HADHA lactylation.

Conclusions:

• Lactylation significantly impacts cardiomyocyte metabolism.
• Lactate-induced HADHA lactylation disrupts mitochondrial function and promotes sepsis-induced cardiac dysfunction.
• Findings suggest novel therapeutic targets for sepsis-induced myocardial depression.