Abstract 16595: NAD+ Precursor Nicotinamide Riboside Alleviates Alcoholic Cardiomyopathy via Mitophagy Induction: A Novel SIRT3-PGAM5-FUNDC1 Axis

Nicotinamide riboside (NR) is widely used as a NAD + precursor vitamin. Supplementation with NR has been shown to protect against metabolic and age-related diseases in mammals. However, the potential effect of NR in alcoholic cardiomyopathy (ACM) has not been well elucidated. This study was designed to examine the effect of NR supplementation on the progression of alcoholic cardiomyopathy. Alcoholic cardiomyopathy was established using chronic alcoholic diet containing 36% kcal from ethanol. Echocardiography and IonOptix MyoCam were used to evaluate cardiac contractile function. Our data revealed that NR alleviated alcohol consumption-induced changes in myocardial and cardiomyocyte contractile function as well as cardiac remodeling. To examine the possible involvement of mitophagy in NR-induced beneficial effects, FUNDC1 -/- mice with mitophagy deficiency were employed. Interestingly, NR-induced beneficial effect against alcoholic cardiomyopathy was partially attenuated in FUNDC1 -/- mice, indicating a role for FUNDC1-mediated mitophagy in NR-offered cardioprotection. In vitro study using H9c2 myoblasts suggested that NR regulated mitochondrial homeostasis through induction of FUNDC1-dependent mitophagy, as suggested by mitophagy-related protein expressions and Mitotracker-LC3 dots overlay. NR treatment enhanced cellular NAD + level, consequently elevated NAD + -dependent mitochondrial sirtuin SIRT3 activity. Using mass spectrum assay and Co-IP, PGAM5, which functions to phosphorylate FUNDC1 at serine 13 (Ser13), was found to interact with and deacetylated by SIRT3 following NR administration. Taken together, our results revealed a protective effect of NR supplementation against alcoholic cardiomyopathy possibly associated with a SIRT3-PGAM5-FUNDC1- dependent regulation of mitophagy. These findings suggested the therapeutic potential of the vitamin B3 precursor of NAD + in the management of alcoholic cardiomyopathy.