Cardiomyocyte mitochondrial mono-ADP-ribosylation dictates cardiac tolerance to sepsis by configuring bioenergetic reserve

The metabolic plasticity of tissues determines the degree and reversibility of organ damage under inflammatory challenges. Still, countermeasures for myocardial metabolic breakdown are absent while treating septic cardiomyopathy (SCM). Nicotinamide adenine dinucleotide signaling is fundamental to cellular metabolic homeostasis and inflammatory reactions. Here we revealed that genetic and pharmacological inactivation of mono-ADP-ribosyl hydrolase MacroD1 enriched in cardiomyocytes counteracted myocardial metabolic impairment, inflammation, dysfunction, and mortality risk induced by lipopolysaccharide and cecal ligation and puncture in mice. Mechanistically, MacroD1 selectively modulated the mitochondrialcomplex I (MCI) activity most vulnerable to early sepsis. Its inhibition enhanced mono-ADP-ribosylation of NDUFB9, an accessory assembly factor of MCI proton-pumping module ND5, and therefore binding to ND5 for preserving MCI activity in sepsis, restraining bioenergetic deficiency, oxidative stress-coupled NLRP3 inflammasome activation, and pyroptosis of cardiomyocytes. Thus, MacroD1 dictates cardiac tolerance to sepsis by configuring MCI-coupled bioenergetic reserve and pyroptosis of cardiomyocytes. Blockade of MacroD1 promises specific prevention of SCM.