Diabetic heart shows preferential secretion of inner mitochondrial membrane proteins in the presence of mitochondrial oxidative stress

Heart disease, including diabetic cardiomyopathy, is a leading cause of mortality in patients with type 2 diabetes (T2D). Defects in heart function are accompanied by marked changes in cardiac metabolism, including dysregulation of lipid and glucose metabolism, mitochondrial dysfunction, and oxidative stress. In addition to these metabolic defects, the heart is an important endocrine organ. However, although T2D has been shown to impact the secretome of liver, skeletal muscle, and adipose tissue (among others), little is known about the secretome of the heart and the influence of T2D on cardiac protein secretion. Using precision-cut heart slices from mice with insulin resistance (20-wk of high-fat feeding) and T2D (db/db mice) compared with their respective controls, we performed mass spectrometry proteomics analysis of cardiac protein secretion and proteins contained within extracellular vesicles (EVs). We reveal striking remodeling of cardiac protein secretion in T2D but not diet-induced insulin resistance. Specifically, we show a marked increase in the secretion of inner mitochondrial membrane (IMM) proteins in T2D, which was accompanied by a disproportional accumulation of outer mitochondrial membrane proteins within the heart. This was associated with increased mitochondrial oxidative stress, selective oxidative damage to IMM proteins, and reduced markers of LC3-mediated mitophagy in the db/db heart, highlighting secretion of mitochondrial components as a potential alternative pathway for mitochondrial quality control. Altogether, this study provides an in-depth proteomics analysis showing remodeling of cardiac protein secretion in T2D and provides insights into a possible link between mitochondrial oxidative stress and the release of mitochondrial components.<b>NEW & NOTEWORTHY</b> Diabetic cardiomyopathy is a leading cause of death in patients with type 2 diabetes (T2D). Here, we show striking remodeling of cardiac protein secretion in mice with T2D, particularly an increase in the release of inner mitochondrial membrane proteins, which was associated with increased oxidative stress within the diabetic heart.