Nicotinamide mononucleotide imparts protection against Doxorubicin-induced cardiotoxicity by maintaining lysosomal acidification
Abstract
Doxorubicin (DOX) blocks the autophagic flux in cardiomyocytes by inhibiting lysosome acidification. The acidic pH of lysosomes is maintained by the V-ATPase pump. NAD+ is an essential cofactor for the maintenance of cellular homeostasis. DOX treatment significantly depletes the NAD+ levels in cardiomyocytes. This study investigated the potential of the NAD+ precursor, nicotinamide mononucleotide (NMN), in preventing DOX-induced cardiotoxicity. DOX induced cell injury and altered the lysosomal pH of H9c2 cells, an in vitro model of cardiomyocytes. These effects of DOX were attenuated by NMN. The protection conferred by NMN was offset by inhibition of V-ATPase activity with bafilomycin A. Furthermore, NMN prevented the DOX induced hyperacetylation of the V-ATPase subunit ATP6V0d1, a critical protein involved in the maintenance of V-ATPase activity. In summary, NMN protects cardiomyocytes from DOX induced toxicity by maintaining the pH of lysosomes. Thus, NMN holds potential in combating the deleterious impacts of Doxorubicin on the heart.