Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Abstract

Significance: Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Recent Advances: Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Critical Issues: Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed ''mitophagy,'' is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. Future Directions: This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically. Antioxid. Redox Signal. 22, 1527Signal. 22, -1544

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

“…In recent years, it has become clear that mitophagy is capable of selectively removing dysfunctional mitochondria to maintain mitochondrial quality and homoeostasis 7, 20. However, the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy is far from clear 13. Here, we investigated the effects of melatonin on mitophagy in mice subjected to a diabetic insult.…”

“…This process accelerates Parkin translocation from the cytosol to the mitochondria,49, 54 and thus ubiquitinates mitochondrial outer membrane proteins to promote recruitment of an autophagosome 55. Other than the PINK1/Parkin pathway, BNIP3, BNIP3L and FUNDC1 are also emerging key players in the regulation of mitophagy 13, 56, 57. A full understanding of the regulatory mechanisms involved in cardiomyocyte mitophagy has yet to be developed, as well as their connection with the onset of diabetes 13.…”

“…Increasing evidence suggests that the cardiovascular complications of diabetes converge on mitochondria as an epicentre for cardiomyocyte damage 12. Cardiomyocytes are particularly susceptible to diabetic insults caused by dysfunctional mitochondria 13, 14. Mitochondria that are damaged during diabetic stress can produce reactive oxygen species (ROS) and release death‐inducing factors, thus augmenting cardiomyocyte injury 14, 15, 16…”

“…Effective clearance of these damaged mitochondria may prevent cardiomyocyte damage induced by diabetes and limit cardiac dysfunction 13, 17. Autophagy is the primary mechanism for mitochondrial quality control and removes whole mitochondria.…”

“…Mitophagy ensures that cardiomyocytes maintain a functional network of mitochondria and provides strong protection against diabetic insults. Mitophagy can be regulated by several pathways during mitochondrial quality control 13, 20, 21. Amongst these, the PINK1/PARKIN pathway is well‐studied and is involved in the labelling of damaged mitochondria for mitophagy degradation 22.…”