SARM1 Regulates BNIP3-Mediated Mitochondrial Quality Control in Diabetic Hearts

Mitochondrial quality control mechanisms such as mitophagy are being linked to NAD + homeostasis in cardiometabolic disease (1).Sterile Alpha and Toll/Interleukin-1 Receptor Motif-containing 1 (SARM1) is an NAD + hydrolase that executes axonal degeneration and regulates mitophagy (2).However, the roles of SARM1 in mitophagy and cardiac disease are unknown.We identified a translational mechanism that SARM1 impairs mitochondrial quality control in cardiometabolic disease.We used streptozotocin to induce diabetic stress (DIA) in mice.For genetic inhibition, we compared diabetic WT mice with SARM1-knockout (KO) mice (Figure A i-v ).For pharmacological inhibition, diabetic WT mice were treated with vehicle (VEH) or SARM1 inhibitor (DSRM-3716) for four weeks, after twelve weeks of diabetic stress (Figure A vi-x ).Streptozotocin induced comparable hyperglycemia in DIA-WT versus DIA-KO, and DIA-VEH versus DIA-DSRM before and after 4-week DSRM treatment (Figure A i,vi ).