Cardiomyocyte mitochondrial mono-ADP-ribosylation dictates cardiac tolerance to sepsis by configuring bioenergetic reserve in male mice.

Summary

Using LPS and CLP murine sepsis models, the authors show that genetic and pharmacologic inhibition of the cardiomyocyte-enriched hydrolase MacroD1 preserves mitochondrial complex I activity, maintains bioenergetic reserve, and reduces pyroptosis. This mechanistic link—enhanced mono-ADP-ribosylation of Ndufb9—attenuates inflammatory injury, improves cardiac function, and lowers mortality.

Key Findings

• Genetic and pharmacological MacroD1 inhibition reduced myocardial metabolic impairment, inflammation, dysfunction, and mortality in LPS and CLP sepsis models.
• MacroD1 modulates mitochondrial complex I; its inhibition preserved complex I activity and cardiomyocyte bioenergetic reserve.
• Enhanced mono-ADP-ribosylation of Ndufb9 linked MacroD1 inhibition to reduced cardiomyocyte pyroptosis.

Clinical Implications

Although preclinical, MacroD1 inhibition could represent a cardioprotective strategy in sepsis, guiding development of selective inhibitors and optimization of timing to preserve mitochondrial function.

Limitations

• Preclinical study in male mice; sex differences and human relevance require validation
• Safety and specificity of MacroD1 inhibition in vivo remain to be established

Future Directions

Develop selective MacroD1 inhibitors; test in large-animal sepsis models; assess sex differences and validate in human cardiac tissues or organoids.