β-Nicotinamide Mononucleotide protects against endotoxemia-induced myocardial injury through Sirt5-dependent desuccinylation of succinate dehydrogenase

During endotoxemia, dysfunction of Succinate Dehydrogenase (SDH) in myocardial tissue serves as a significant contributor to impaired cardiac function. Previous study has suggested that Sirtuin 5 (SIRT5)-mediated SDH desuccinylation exerts a cardioprotective effect. However, in the context of endotoxemia, the level of nicotinamide adenine dinucleotide (NAD⁺), an essential co-substrate for SIRT5 in myocardial tissue, is diminished, leading to the inability to maintain SIRT5 activity. This study aims to investigate whether supplementation with the NAD⁺ precursor β-nicotinamide mononucleotide (NMN) ameliorates endotoxemia-induced myocardial injury by activating Sirt5-mediated desuccinylation of SDH. Mice were intraperitoneally administered NMN (500 mg/kg) for 1, 7, 14, 21, and 28 consecutive days. Myocardial NAD⁺ levels gradually increased to a saturation level (peaking at 14 days), with no obvious adverse effects. In LPS-induced myocardial injury, NMN supplementation significantly improved survival rates, reduced serum cardiac troponin I (cTnI), enhanced cardiac function, restored ATP production, downregulated pro-inflammatory cytokines, and alleviated oxidative damage. We further discovered that NMN corrected the aberrant catalytic function of SDH, reduced succinate accumulation, and increased fumarate levels. Mechanistically, NMN supplementation specifically reduced SDH succinylation (but not acetylation) and promoted the binding of SIRT5 to SDH. After cardiomyocyte-specific knockdown of SIRT5, the protective effects of NMN on SDH desuccinylation and myocardial protection were significantly attenuated. In summary, NMN supplementation elevates myocardial NAD⁺ levels, promotes Sirt5-mediated SDH desuccinylation, corrects succinate metabolism disorder, and thereby mitigates endotoxemia-induced myocardial injury.

Myocardial injury; Nicotinamide mononucleotide; Sirt5; Succinate dehydrogenase; Succinylation.