Peroxisomal Dysfunction in Age-Related Diseases

Abstract

Peroxisomes carry out many key functions related to lipid and reactive oxygen species (ROS) metabolism. The fundamental importance of peroxisomes for health in humans is underscored by the existence of devastating genetic disorders caused by impaired peroxisomal function or lack of peroxisomes. Emerging studies suggest that peroxisomal function may also be altered with aging and contribute to the pathogenesis of a variety of diseases, including diabetes and its related complications, neurodegenerative disorders, and cancer. With increasing evidence connecting peroxisomal dysfunction to the pathogenesis of these acquired diseases, the possibility of targeting peroxisomal function in disease prevention or treatment becomes intriguing. Here, we review recent developments in understanding the pathophysiological implications of peroxisomal dysfunctions outside the context of inherited peroxisomal disorders.

Keywords: aging; neurodegeneration; peroxisome; pexophagy; reactive oxygen species.

Figure 1. Metabolic Functions of Peroxisomes

Peroxisomes perform a variety of lipid metabolic functions. Catabolic functions include beta oxidation of VLCFAs and alpha oxidation of 3-methyl branched FAs, whereas anabolic functions include ether lipid synthesis and bile acid synthesis. Peroxisomes are also involved in the metabolism of reactive oxygen species. Abbreviations: DHAP, dihydroxyacetone phosphate; FA, fatty acid; G3P, glycerol 3-phosphate; ROS, reactive oxygen species; VLCFA, very long chain fatty acid.

Figure 2. Removal of Dysfunctional Peroxisomes by Pexophagy

ROS-activated ATM kinase both signals to mTORC1 to inhibit its suppression of autophagy and phosphorylates Pex5 to promote its ubiquitination and its subsequent binding of p62, thus targeting the peroxisome for degradation. Abbreviations: ATM, ataxia–telangiectasia mutated; LC3, microtubule-associated protein light chain 3; mTORC1, mammalian target of rapamycin complex 1; Pex5, peroxisomal biogenesis factor 5; ROS, reactive oxygen species; TSC, tuberous sclerosis complex; Ub, ubiquitinated; ULK1, Unc-51-like autophagy activating kinase 1.

Figure 3. Peroxisomal Dysfunction in Age-Related Diseases

Decreased expression or peroxisomal localization of proteins involved in ROS and lipid metabolism is observed in metabolic and neurodegenerative disorders. Increased expression or peroxisomal compartmentalization of different metabolic enzymes is observed in cancer. Abbreviations: AGPS, alkylglycerone phosphate synthase; FAO, fatty acid oxidation; MCT2, monocarboxylate transporter 2; ROS, reactive oxygen species; VLCFA, very long chain fatty acid.