Mitophagy Disequilibrium, a Prominent Pathological Mechanism in Metabolic Heart Diseases

Abstract

With overall food intake among the general population as high as ever, metabolic syndrome (MetS) has become a global epidemic and is responsible for many serious life-threatening diseases, especially heart failure. In multiple metabolic disorders, maintaining a dynamic balance of mitochondrial number and function is necessary to prevent the overproduction of reactive oxygen species (ROS), which has been proved to be one of the important mechanisms of cardiomyocyte injury due to the mismatching of oxygen consumption and mitochondrial population and finally to heart failure. Mitophagy is a process that eliminates damaged or redundant mitochondria. It is mediated by a series of signaling molecules, including PINK, parkin, BINP3, FUNDC1, CTSD, Drp1, Rab9 and mTOR. Meanwhile, increasing evidence also showed that the interaction between ferroptosis and mitophagy interfered with mitochondrial homeostasis. This review will focus on these essential molecules and pathways of mitophagy and cell homeostasis affected by hypoxia and other stimuli in metabolic heart diseases.

Keywords: BNIP3; Bcl-2/E1B19kDa-interacting protein; FUN14 domain-containing protein 1; FUNDC1; PINK; PTEN induced putative kinase; ferroptosis; metabolic heart diseases; metabolic syndrome; mitophagy; parkin.

Figure 1

Mitophagy disequilibrium acts as a prominent pathological mechanism in metabolic heart diseases. Hypoxia and subsequent metabolic disorders contribute to oxidative stress injury and abnormal mitophagy in heart. Drp1 induces the fission of damaged mitochondria (in pink) from healthy mitochondria (in blue); Parkin and PINK response to the stimuli of ROS produced by damaged mitochondria and induce mitophagy; Receptors locating at the OMM, like BNIP3, NIX, FUNDC1 and AMBRA1, bind with LC3 proteins to mediate autophagosome formation; Ubiquitin ligases of MUL1 and MG53 recruit more phagophore to assist in mitophagy implement; mTOR plays a negative effect to regulate phagophore formation. In addition, ferroptosis has recently been found to be involved in and interact with mitophagy. Abnormalities of above molecules and pathways of mitophagy become critical nodes of heart dysfunction occurrence and development. Restoring mitochondrial homeostasis by modulating these targets may be an important strategy worthy of in-depth study and then accelerate the development of novel therapies for mitochondria-related metabolic heart diseases.