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Review
. 2022 Jan 19;11(2):192.
doi: 10.3390/antiox11020192.

Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging

Jinoh Kim  1 , Hua Bai  1
Affiliations
Review

Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging

Jinoh Kim et al. Antioxidants (Basel). .

Abstract

Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. Given the essential role of peroxisomes in cellular homeostasis, peroxisomal dysfunction has been linked to various pathological conditions, tissue functional decline, and aging. In the past few decades, a variety of cellular signaling and metabolic changes have been reported to be associated with defective peroxisomes, suggesting that many cellular processes and functions depend on peroxisomes. Peroxisomes communicate with other subcellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. These inter-organelle communications are highly linked to the key mechanisms by which cells surveil defective peroxisomes and mount adaptive responses to protect them from damages. In this review, we highlight the major cellular changes that accompany peroxisomal dysfunction and peroxisomal inter-organelle communication through membrane contact sites, metabolic signaling, and retrograde signaling. We also discuss the age-related decline of peroxisomal protein import and its role in animal aging and age-related diseases. Unlike other organelle stress response pathways, such as the unfolded protein response (UPR) in the ER and mitochondria, the cellular signaling pathways that mediate stress responses to malfunctioning peroxisomes have not been systematically studied and investigated. Here, we coin these signaling pathways as "peroxisomal stress response pathways". Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important and emerging areas of peroxisome research.

Keywords: ER stress; acetyl-CoA; apoptosis; mitochondrial dysfunction; peroxisome; pexophagy; plasmalogen; reactive oxygen species.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular responses to peroxisomal dysfunction. Impaired peroxisomal function elicits cellular responses such as the impaired ROS homeostasis, dysregulated lipid metabolism, mitochondrial dysfunction, altered gene expression, pexophagy, elevated ER stress, and apoptosis.
Figure 2
Figure 2
Peroxisome-organelle membrane contact sites and their roles in organelle functions. Peroxisomes’ contact with mitochondria involves (1) peroxisomal Pex11 and mitochondrial Mdm34, (2) peroxisomal Pex34 and an unknown mitochondrial protein, (3) mitofusin Fzo1 on both peroxisome and mitochondria, and (4) peroxisomal ACBD2/ECI2 and mitochondrial TOMM20. The interaction between peroxisomes and the ER involves (1) peroxisomal ACBD5 and resident ER protein VAPB and (2) peroxisomal ABCD3 and ER protein ATF6α upon Ceapin treatment. In mammalian cells, the contact between peroxisomes and lysosomes involves phospholipid PI(4,5)P2 on the peroxisomal membrane and lysosomal Syt7. Abbreviations: Pex11, peroxin 11; Mdm34, mitochondrial distribution and morphology protein 34; Pex34, peroxin 34; Fzo1, mitofusin; ACBD2/ECI2, acyl-coenzyme A-binding domain or enoyl-CoA-δ isomerase 2; TOMM20, translocase of outer mitochondrial membrane 20; ACBD5, acyl-CoA binding domain-containing protein 5; VAPB, vesicle-associated membrane protein-associated protein B/C; ABCD3, ATP binding cassette subfamily D member 3; ATF6, activating transcription factor 6; PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; Syt7, synaptotagmin VII.
Figure 3
Figure 3
Metabolic and molecular signaling pathways mediate peroxisome-organelle crosstalk in response to peroxisomal dysfunction. (1) Peroxisome-nucleus: Peroxisomal dysfunction activates nuclear gene transcription through the transcription factors PPARα, AP-1, or Hnf4. The accumulation of long-chain fatty acids (LCFAs) activates PPARα to upregulate LONP2 and CAT expression to restore peroxisomal function (Blue arrow). Elevated ROS activates JNK signaling and AP-1 to induce the transcription of the pro-inflammatory cytokine IL-6. Peroxisomal dysfunction activates Hnf4 through unknown mechanisms to induce the expression of lipase 3 (Lip3), which leads to excessive free fatty acids (FFA) in the cytoplasm. FFAs hyper-activate Hnf4 via a positive feedback loop. (2) Peroxisome-mitochondrion: Peroxisomal dysfunction causes mitochondrial swelling, mitochondrial ROS generation, mitochondrial DNA (mtDNA) damage, disruption of oxidative phosphorylation (OXPHOS), and decreased inner membrane potential. Excessive ROS and elevated VLCFA are the potential signaling molecules that mediate the peroxisome-mitochondrion crosstalk. Peroxisomal dysfunction decreases plasmalogen, resulting in the inhibition of mitochondrial fission. (3) Peroxisome-ER: Peroxisomal dysfunction activates PERK signaling through unknown mechanisms to increase the phosphorylation of eIF2α and ATF4 induction. (4) Peroxisome-lysosome: Peroxisomal dysfunction due to the loss of Acox1 decreases peroxisome-derived acetyl-CoA, resulting in Raptor acetylation and lysosome localization of mTOR, leading to ULK1 activation and elevated lipophagy. Abbreviations: PPARα, peroxisome proliferator activated receptor alpha; AP-1, activator protein-1; Hnf4, hepatocyte nuclear factor 4; LONP2, lon peptidase 2; CAT, catalase; upd3, unpaired 3; IL-6, interleukin 6; Lip3, lipase 3; ROS, reactive oxygen species; JNK, Jun N-terminal kinase; VLCFAs, very-long-chain fatty acids; PERK, protein kinase RNA-like endoplasmic reticulum kinase; eIF2α, eukaryotic translation initiation factor 2a, ATF4, activating transcription factor 4; mTOR, mechanistic target of rapamycin kinase; ULK1, Unc-51-like autophagy-activating kinase 1.
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