Peroxisomes as cellular adaptors to metabolic and environmental stress

Abstract

Peroxisomes are involved in multiple metabolic processes, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism. Recent studies suggest that peroxisomes are critical mediators of cellular responses to various forms of stress, including oxidative stress, hypoxia, starvation, cold exposure, and noise. As dynamic organelles, peroxisomes can modulate their proliferation, morphology, and movement within cells, and engage in crosstalk with other organelles in response to external cues. Although peroxisome-derived hydrogen peroxide has a key role in cellular signaling related to stress, emerging studies suggest that other products of peroxisomal metabolism, such as acetyl-CoA and ether lipids, are also important for metabolic adaptation to stress. Here, we review molecular mechanisms through which peroxisomes regulate metabolic and environmental stress.

Keywords: ether lipid; lipid metabolism; peroxisome; plasmalogen; reactive oxygen species; stress.

Figure 1.. Crosstalk between peroxisomes and other organelles.

Peroxisomal biogenesis and functions involves inter-organelle communication. De novo formation of peroxisomes involves fusion of precursor vesicles derived from the ER and mitochondria. Peroxisomes closely interact and exchange lipids with lipid droplets. Synthesis of ether lipids, such as plasmalogens, initiates in peroxisomes but is completed in the ER. The ER-peroxisome metabolite exchange may be assisted by the bridge formed by the membrane proteins VAPA, VAPB and ACBD5. Peroxisomes are also closely associated with mitochondria. Peroxisome-derived plasmalogens are found in mitochondrial membranes and may be involved in mitochondrial dynamics. Mitochondria help to further oxidize chain-shortened fatty acids produced by peroxisomal fatty acid oxidation. Peroxisomes also interact with lysosomes through the membrane protein Syt7, which promotes transfer of free cholesterol from lysosomes to peroxisomes. Abbreviations: ER, endoplasmic reticulum; VAPA and VAPB, VAMP-associated proteins A and B; ACBD5, acyl-CoA binding domain containing protein 5; Syt7, synaptotagmin 7.

Figure 2.. Role of peroxisomes in nutrient deprivation-induced lipid hydrolysis.

In adipocytes, fasting stimulates interaction between peroxisomes and lipid droplets (LD) by increasing kinesin-like protein KIFC3-dependent movement of peroxisomes toward LDs. The peroxisomal biogenesis factor Pex5 interacts with ATGL and recruits it to peroxisome-LD contact sites to induce lipolysis. The fatty acids liberated from hydrolysis of LDs are mobilized and taken up by peripheral tissues, such as the liver. In hepatocytes, these fatty acids are reesterified to triglyceride and stored in lipid droplets. Peroxisomes inhibit hydrolysis of these lipids by blocking lipophagy. This involves peroxisomal fatty acid oxidation-mediated production of acetyl-CoA, which promotes acetylation of Raptor, a component of mTORC1. Activated mTORC1 inhibits lipophagy. Fatty acids released by lipophagic hydrolysis of triglycerides may also be oxidized in peroxisomes to generate acetyl-CoA, potentially reflecting a negative feedback mechanism to limit hydrolysis of intracellular lipid stores. Abbreviations: ATGL, adipose triglyceride lipase; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; TG, triglyceride.

Figure 3.. Role of peroxisomes in response to various stressors.

Cold induces peroxisomal biogenesis in brown fat results in increased production of plasmalogens, a form of ether lipids that are a component of mitochondrial membranes. Plasmalogens promote cold-induced mitochondrial fission to support thermogenesis. Hypoxic stress also promotes synthesis of ether lipids, which help to reduce membrane rigidity associated with low oxygen tension and improve cellular fitness. Peroxisomes are involved in innate immune response to viral infections, but some viruses have evolved a strategy to escape the antiviral effect mediated by peroxisomes. Viruses, such as HMCV promote peroxisomal production of ether lipids to support secondary envelopment of infectious particles. Peroxisomes play a protective role in bacterial infections through requirement of peroxisomal ROS and lipid metabolism in phagocytosis. Noise promotes ROS production and oxidative damage, leading to auditory hair cell damage and hearing loss. Pejvakin mediated-pexophagy is activated by noise-induced ROS in auditory hair cells to clear damaged peroxisomes, paving the way for peroxisome biogenesis. Pejvakin deficiency leads to noise-induced hearing loss. Abbreviations: DHA, docosahexaenoic acid; HMCV, human cytomegalovirus; RNS, reactive nitrogen species; ROS, reactive oxygen species.

Box 1, Figure I.. Peroxisomal biogenesis pathway.

De novo formation of peroxisomes requires fusion of a pre-peroxisomal vesicle derived from the ER with a vesicle derived from the mitochondria, followed by import of peroxisomal matrix and membrane proteins. Abbreviations: PMP, peroxisomal membrane protein; PTS1, peroxisomal targeting sequence 1-containing matrix protein; PTS2, peroxisomal targeting sequence 2-containing matrix protein; Ub, ubiquitination.

Box 2, Figure I.. Peroxisomal β-oxidation pathway.

Very long chain fatty acids (VLCFA) are activated to acyl-CoA and imported by peroxisomes for β-oxidation. Each cycle of fatty acid oxidation shortens the acyl chain by 2 carbons with the thiolytic cleavage of the terminal acetyl-CoA.

Box 3, Figure I.. Ether lipid synthetic pathway.

The initial steps of ether lipid synthesis take place in peroxisomes, generating 1-O-alkyl glycerol-3-phosphate (AGP), a precursor of ether lipids. The subsequent steps take place in the ER. Peroxisomes can also generate lysophophatidic acid (LPA), a precursor of conventional diacylphospholipids.