Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders

Abstract

Metabolic disorders include metabolic syndrome, obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. Due to unhealthy lifestyles such as high-calorie diet, sedentary and physical inactivity, the prevalence of metabolic disorders poses a huge challenge to global human health, which is the leading cause of global human death. Mitochondrion is the major site of adenosine triphosphate synthesis, fatty acid β-oxidation and ROS production. Accumulating evidence suggests that mitochondrial dysfunction-related oxidative stress and inflammation is involved in the development of metabolic disorders. Mitophagy, a catabolic process, selectively degrades damaged or superfluous mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial function. It is considered to be one of the major mechanisms responsible for mitochondrial quality control. Growing evidence shows that mitophagy can prevent and treat metabolic disorders through suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. In the past decade, in order to expand the range of pharmaceutical options, more and more phytochemicals have been proven to have therapeutic effects on metabolic disorders. Many of these phytochemicals have been proved to activate mitophagy to ameliorate metabolic disorders. Given the ongoing epidemic of metabolic disorders, it is of great significance to explore the contribution and underlying mechanisms of mitophagy in metabolic disorders, and to understand the effects and molecular mechanisms of phytochemicals on the treatment of metabolic disorders. Here, we investigate the mechanism of mitochondrial dysfunction in metabolic disorders and discuss the potential of targeting mitophagy with phytochemicals for the treatment of metabolic disorders, with a view to providing a direction for finding phytochemicals that target mitophagy to prevent or treat metabolic disorders.

Keywords: inflammatory response; metabolic disorders; mitochondrial dysfunction; mitophagy; oxidative stress; phytochemicals.

FIGURE 1

Diagram illustrates the mechanisms of mitophagy. Damaged and dysfunctional mitochondria will be segregated by autophagic membranes. And the autophagosome fuses with lysosome to form autophagolysosome, in which mitochondria will be degraded by lysosomal enzyme and the degradation products will be used as substrates for energy metabolism.

FIGURE 2

Diagram illustrates the signaling pathway regulating mitophagy. In damaged mitochondria, PINK1 located in the outer mitochondrial membrane, can phosphorylate Ser65 in the ubiquitin and ubiquitin-like domain of Parkin and further facilitates its localization from the cytosol to the outer mitochondrial membrane. Moreover, Parkin can also promote the ubiquitination of MFN1, MFN2, TOM20 and VDAC to further induce mitophagy. In response to hypoxia and nutritional deprivation, BNIP3 and NIX-mediated mitophagy is induced. In this process, BNIP3 and NIX directly interact with LC3 to enhance mitophagy. And BNIP3 and NIX also bind to the BH3 domain of Beclin1 to activate mitophagy. What’s more, similar to BNIP3/NIX, FUNDC1 interacts with LC3 through its LIR to activate mitophagy under hypoxic conditions.

FIGURE 3

Phytochemical activates mitophagy to treat metabolic disorders. Phytochemical activates PINK1-Parkin-dependent mitophagy and BNIP3/NIX-dependent mitophagy to treat metabolic disorders. In PINK1-Parkin-dependent mitophagy, PINK1 phosphorylates Ser65 in the ubiquitin and ubiquitin-like domain of Parkin and further facilitates its localization from the cytosol to the outer mitochondrial membrane of dysfunctional mitochondria. Moreover, Parkin can further promote the ubiquitination of MFN1, MFN2, TOM20 and VDAC, which can be identified by autophagy receptors p62 and then bind to LC3 positive autophagosomes to promote dysfunctional mitochondria to be captured by autophagosomes. Additionally, BNIP3 and NIX are easier to bind to Bcl-2 and Bcl-XL than Beclin1, which causes the release of Beclin-1 from Beclin1-Bcl-2-Bcl-XL complexes and subsequently induces mitophagy.

FIGURE 4

Mechanisms of phytochemical-mediated mitophagy in the treatment of metabolic disorders. Phytochemical activates mitophagy to degrade damaged mitochondria to prevent the production of mitochondrial ROS which can trigger oxidative stress and inflammatory response, and eventually preventing and treating metabolic diseases.