Abstract 21: Diabetic Ketoacidosis Compromises Cardiac Mitochondrial Quality Control in Humans

Abstract

Mitochondrial injury plays a key role in the pathogenesis of diabetic cardiomyopathy, a risk factor for heart failure in diabetic populations. Dysfunctional mitochondria are eliminated through several coordinated mitochondrial quality control mechanisms including the autophagy-lysosome degradation pathway, a process termed mitophagy. Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of type 1 diabetes. We have shown that adolescents and young adults with uncomplicated DKA mount a robust systemic inflammatory response which is associated with diastolic cardiac abnormality. However, it remains unknown if cardiac abnormality in patients with DKA is correlated with altered mitochondrial quality control processes. In the present study, using immunofluorescent labeling and confocal microscopic imaging, we examined a series of proteins involved in autophagy, mitophagy and mitochondrial dynamics in paraffin-embedded autopsy heart tissues from young people without or with fatal DKA. We found that the expression levels of beclin 1, microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein (LAMP) 1/2 are not changed, but that of p62 is increased in the heart of DKA patients, suggesting a decreased autophagy. Also, the expression levels and localization of Pink1, parkin and Rab9, three potential regulators of mitophagy, are markedly changed, indicating an altered mitophagy in the DKA heart. In addition, mitochondrial fusion and fission proteins (Mitofusin 2, Opa1, Drp1 and Fis1) are all altered to varying degrees in the DKA heart, which is accompanied by increased mitochondrial fragmentation, oxidative injury and apoptosis (TUNEL positive cells). Together, these findings demonstrate that the mitochondrial quality control mechanisms are not operating normally in the heart of patients with DKA. Therefore, therapeutic strategies that aim to improve the efficiency of the mitochondrial quality control may have the potential to reduce diabetic cardiac injury and heart failure in young type 1 diabetic patients.