Abstract Body: Diabetic cardiomyopathy (DMCM) is a major cause of death in diabetic patients. Emerging evidence shows that mitochondrial dysfunction contributes to heart failure in diabetes. However, the molecular mechanisms of mitochondrial dysfunction mediating heart failure in diabetes are still poorly understood. The current study aimed to investigate the role of mitochondrial ribosomal protein L7/L12 (MRPL12) in human and mouse models of type II diabetes (db/db mice, and high-fat diet fed (HFD) mice) with or without induction of myocardial infarction (MI). Mitochondrial respiration was measured by using sea horse and mitochondrial membrane potential was measured by using confocal microscopy. Data was analyzed by using the mean of the groups was compared using a student t-test (for 2 groups) and ANOVA. We found increased MRPL12 levels in diabetic patients with ischemic heart disease compared to non-diabetic patients. Further we found elevated MRPL12 levels in the LV tissue of HFD fed mice with MI compared to low-fat diet-fed mice with MI. With the overexpression of MRPL12 under hyperglycemic conditions, the level of oxidative phosphorylation (OXPHOS) was found downregulated, but cellular ATP and human cardiomyocyte cell death remained unchanged, However, there was notable impairment in mitochondrial membrane potential (MMP) in hyperglycemia condition, along with changes in basal respiration oxygen consumption rate (OCR) and maximal respiratory capacity OCR. Overall, our results suggest MRPL12 may have a compensatory role in the diabetic hearts with ischemic heart disease. Therefore, our finding proposes new insights into the role of MRPL12 in the pathophysiology of MI in diabetes.