Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.

Aerobic respiration, although metabolically advantageous in O2-rich environments, can be detrimental to the cell when O2 is not fully reduced resulting in cytotoxic reactive oxygen species (ROS) production. Cytochrome c oxidase subunit 4 (COX-4) is primarily responsible for fully reducing O2 during metabolism and exists as COX4-1 and COX4-2 isoforms. The former exists in normoxia, but is replaced by the latter in hypoxia. This change is brought about by two mechanisms, the first involving regulation by hypoxia inducible factor 1 (HIF-1), which directly upregulates COX4-2 and indirectly degrades COX4-1. The second mechanism involves an oxygen responsive element (ORE), which upregulates COX4-2 in a HIF-1 independent manner. The convergence of two unrelated pathways to regulate COX4-1 and COX4-2 would allow cells to optimize their metabolic profile within an environment experiencing varying O2, such as Earth’s early atmosphere in the case of primitive aerobic bacteria or in multicellular organisms where O2 levels vary between tissues such as lung tissue.