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

The metabolic flexibility of tissues dictates the extent and reversibility of organ damage during inflammatory challenges. However, there are currently no countermeasures for myocardial metabolic breakdown in the treatment of septic cardiomyopathy (SCM). Nicotinamide adenine dinucleotide (NAD+) signaling is crucial for maintaining cellular metabolic homeostasis and modulating inflammatory responses. Through the use of single-cell sequencing technology, specifically the 10x Genomics scRNAseq approach, we have investigated the role of NAD+ signaling-related genes in SCM. Our findings reveal that both genetic and pharmacological inhibition of the mono-ADP-ribosyl hydrolase MacroD1, which is highly expressed in cardiomyocytes, can effectively counteract the myocardial metabolic impairment, inflammation, dysfunction, and mortality risk triggered by lipopolysaccharide exposure and cecal ligation and puncture in mice. Overall design: We applied lipopolysaccharide via intraperitoneal injection in mice to establish a septic cardiomyopathy model, and harvested the hearts 18 hours post-administration. The cardiac tissues were enzymatically digested into a single-cell suspension and subjected to single-cell sequencing.