Role of Mitophagy in Regulating Intestinal Oxidative Damage

Abstract

The mitochondrion is also a major site for maintaining redox homeostasis between reactive oxygen species (ROS) generation and scavenging. The quantity, quality, and functional integrity of mitochondria are crucial for regulating intracellular homeostasis and maintaining the normal physiological function of cells. The role of oxidative stress in human disease is well established, particularly in inflammatory bowel disease and gastrointestinal mucosal diseases. Oxidative stress could result from an imbalance between ROS and the antioxidative system. Mitochondria are both the main sites of production and the main target of ROS. It is a vicious cycle in which initial ROS-induced mitochondrial damage enhanced ROS production that, in turn, leads to further mitochondrial damage and eventually massive intestinal cell death. Oxidative damage can be significantly mitigated by mitophagy, which clears damaged mitochondria. In this review, we aimed to review the molecular mechanisms involved in the regulation of mitophagy and oxidative stress and their relationship in some intestinal diseases. We believe the reviews can provide new ideas and a scientific basis for researching antioxidants and preventing diseases related to oxidative damage.

Keywords: PINK1-Parkin; ROS; intestinal damage; mitophagy; oxidative stress.

Figure 1

Molecular mechanism of mitophagy. In the PINK1–Parkin pathway, decreased MMP leads to the accumulation of PINK1 to the OMM, promoting Parkin recruitment. Parkin ubiquitinates several outer membrane components, and PINK1 then phosphorylates the poly-Ub chains. The poly-Ub chains on the OMM allow the interaction of mitochondria with LC3 for autophagic degradation through specific adaptors, such as p62, OPTN, TAX1BP1, and NDP52. Gp78, SMURF1, MUL1, SIAH1 and ARIH1 represent alternative E3 ubiquitin ligases targeting OMM proteins before mitophagy. Mitochondrial dynamics and motility are modulated by the PINK1–Parkin pathway by targeting MFN, DRP1 and Miro for degradation by proteasomes. In receptor-mediated mitophagy, BNIP3, NIX and FUNDC1 mitophagy receptors mediate mitochondrial elimination indirectly by interacting with LC3.

Figure 2

Administration of drugs, which regulate mitochondrial ROS production and mitophagy, improves organismal homeostasis and various disease conditions.