Abstract
Peroxisomes play essential roles in diverse cellular metabolism functions, and their dynamic homeostasis is maintained through the coordination of peroxisome biogenesis and turnover. Pexophagy, selective autophagic degradation of peroxisomes, is a major mechanism for removing damaged and/or superfluous peroxisomes. Dysregulation of pexophagy impairs the physiological functions of peroxisomes and contributes to the progression of many human diseases. However, the mechanisms and functions of pexophagy in mammalian cells remain largely unknown compared to those in yeast. This review focuses on mammalian pexophagy and aims to advance the understanding of the roles of pexophagy in human health and diseases. Increasing evidence shows that ubiquitination can serve as a signal for pexophagy, and ubiquitin-binding receptors, substrates, and E3 ligases/deubiquitinases involved in pexophagy have been described. Alternatively, pexophagy can be achieved in a ubiquitin-independent manner. We discuss the mechanisms of these ubiquitin-dependent and ubiquitin-independent pexophagy pathways and summarize several inducible conditions currently used to study pexophagy. We highlight several roles of pexophagy in human health and how its dysregulation may contribute to diseases.
Highlights
Peroxisomes are single-membrane organelles present in virtually all eukaryotic cells.In mammalian cells, they play essential roles in diverse cellular metabolism, such as β-oxidation of fatty acids, redox homeostasis, and the biosynthesis of bile acids and plasmalogens [1]
By using HaloTag technology to examine peroxisome dynamics, it was found that peroxisomes in cultured mammalian cells have a half-life of 1.5~2 days under basal growth conditions and treatment with 3-methyladenine, an inhibitor of the class III phosphoinositide 3-kinase (PI3K) complex, prevents the degradation of peroxisomes, suggesting that autophagy is involved in peroxisome turnover [7]
The study showed that the autophagy receptors NBR1 and SQSTM1 localize to peroxisomes and are degraded by pexophagy, suggesting that NBR1 and p62 may be involved in HIF-2α-mediated pexophagy
Summary
Peroxisomes are single-membrane organelles present in virtually all eukaryotic cells In mammalian cells, they play essential roles in diverse cellular metabolism, such as β-oxidation of fatty acids, redox homeostasis, and the biosynthesis of bile acids and plasmalogens [1]. Three independent mechanisms have been proposed for peroxisome degradation in mammalian cells: the Lon protease system, autolysis, and pexophagy [14] Excess matrix proteins, such as β-oxidation enzymes, can be digested through the Lon protease system. By comparison to autophagy-deficient mice, it is found that 70~80% of proliferated peroxisomes are degraded through pexophagy, and the remaining peroxisomes are removed by the Lon protease system and autolysis mechanisms [15,16]. We focus here on recent advances in our understanding of pexophagy in mammalian cells
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