Pexophagy: Molecular Mechanisms and Implications for Health and Diseases

Abstract

Autophagy is an intracellular degradation pathway for large protein aggregates and damaged organelles. Recent studies have indicated that autophagy targets cargoes through a selective degradation pathway called selective autophagy. Peroxisomes are dynamic organelles that are crucial for health and development. Pexophagy is selective autophagy that targets peroxisomes and is essential for the maintenance of homeostasis of peroxisomes, which is necessary in the prevention of various peroxisome-related disorders. However, the mechanisms by which pexophagy is regulated and the key players that induce and modulate pexophagy are largely unknown. In this review, we focus on our current understanding of how pexophagy is induced and regulated, and the selective adaptors involved in mediating pexophagy. Furthermore, we discuss current findings on the roles of pexophagy in physiological and pathological responses, which provide insight into the clinical relevance of pexophagy regulation. Understanding how pexophagy interacts with various biological functions will provide fundamental insights into the function of pexophagy and facilitate the development of novel therapeutics against peroxisomal dysfunction-related diseases.

Keywords: peroxisomal disorder; peroxisomal protein; peroxisome; pexophagy; selective autophagy receptor.

Fig. 1. A model of peroxisomal biogenesis

Peroxisome biogenesis is coordinated by two different pathways, de novo biogenesis and the ‘growth and division’. First, peroxisomes can be formed by peroxisome assembly and maturation of pre-peroxisomal vesicles originated from ER or mitochondria, which contain pre-peroxisomal carriers, including PEX3 and PEX16. Second, peroxisomes can proliferate the numbers by a growth and division progress from existing peroxisomes. PEX11 and Drp1 proteins mediate elongation and fission of the peroxisomes.

Fig. 2. Pexophagy regulators

Pexophagy is triggered by both stress conditions and peroxisomal dysfunctions. Ubiquitination of PMPs, such as peroxins and PMP70, promotes pexophagy. Both NBR1 and p62 act as autophagy adaptor proteins, which interact with PMPs and sequester target peroxisome into autophagosomes. Under conditions of oxidative stress, the ataxia-telangiectasia mutation activates pexophagy by phosphorylating PEX5, leading to its ubiquitination. Pexophagy may be regulated by an unidentified protein (X).