SARM1 NAD⁺Hydrolase Promotes Mitochondrial Defects in Diabetic Cardiomyopathy by Impairment of Mitophagy

Diabetes is a major risk factor for heart disease. Decline of NAD + , an essential redox cofactor in cellular metabolism, is frequently reported in cardiometabolic disease. We and others have earlier shown that NAD + repletion by enhancing its synthesis can attenuate adverse cardiometabolic outcomes. In this study, our objective was to determine if restoration of cardiac NAD + pool by inhibiting NAD + consumption can protect against diabetic cardiomyopathy. SARM1 is a mitochondria-associated NAD + hydrolase that promotes axonal degeneration through NAD + decline and mitochondrial dysfunction. However, its role in the diabetic heart has never been reported. We hypothesized that SARM1 promotes diabetic cardiomyopathy through mitochondrial defects. To test the effect of genetic deficiency of SARM1 on diabetic cardiomyopathy, wild-type (WT) and SARM1-knockout (KO) mice were injected with streptozotocin to induce type 1 diabetes (T1D). 16-week T1D stress caused progressive decline in systolic and diastolic function in WT mice, as measured by echocardiography. T1D-KO mice had attenuated systolic and diastolic dysfunction, despite similar hyperglycemia. Mitochondria of T1D-WT hearts had 50% reduction in ADP-driven (OXPHOS) respiration, which was reversed in T1D-KO. Cardiac tissue NAD + decline in T1D-WT hearts was restored in T1D-KO, while cardiac mitochondrial NAD + decline in T1D-WT was not reversed in T1D-KO, suggesting regulation of extra-mitochondrial NAD + pools by SARM1. Downregulation of OXPHOS genes and Tfam protein in T1D hearts was not changed by SARM1 deletion, indicating its minor role in mitochondrial biogenesis. T1D-WT hearts had increased mitochondrial LC3B, BNIP3 mRNA and protein, indicating increased activation of receptor-mediated mitophagy. In electron microscopy, T1D-WT hearts showed fragmented mitochondria with disrupted cristae. SARM1 deficiency reversed the upregulations of LC3B and BNIP3 in T1D-KO hearts, and reduced the accumulation of damaged mitochondria. BNIP3 is reported to be induced by hypoxia in the heart and NAD + decline can promote a pseudohypoxic state. T1D-WT hearts showed upregulation of hypoxia-inducible factor-1 α (HIF1α) mRNA levels and its target genes, which was attenuated in T1D-KO hearts. To test the therapeutic potential of SARM1 inhibition, after 12 weeks of STZ-induced T1D stress, WT mice were treated with the SARM1 inhibitor DSRM-3716 or vehicle (VEH) for 4 weeks. DSRM-3716 reversed pre-existing systolic and diastolic dysfunction in T1D mice. The decline in ADP-driven respiration observed in T1D-VEH heart mitochondria was reversed in T1D-DSRM mitochondria. T1D-induced mitochondrial NAD + decline was not reversed by DSRM-3716. In H9c2 cells overexpressing SARM1, cytosolic NAD + decline was observed using a genetically-encoded compartmental NAD + biosensor, and was reversed by DSRM-3716. Taken together, our data implicate SARM1 as the mediator of impaired receptor (BNIP3)-mediated mitophagy driven by cytosolic NAD + decline and pseudohypoxic state in diabetic hearts. In conclusion, SARM1 promotes mitochondrial and functional defects in diabetic hearts, driven by cytosolic NAD + decline and dysregulated receptor-mediated mitophagy. We further plan to investigate the translational potential of SARM1 inhibition and underlying molecular mechanisms. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.