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.
Highlights
Eukaryotic cells contain a variety of membrane-enclosed organelles
The cell death phenotypes were rescued by the overexpression of Pex3 or Pex5 in the corresponding knockout mouse embryonic fibroblast (MEF), suggesting that peroxisomal dysfunction modulates caspase activity and apoptosis [126]
Peroxisomes were shown to play an important role in ferroptosis, a unique process of nonapoptotic cell death caused by the accumulation of iron-dependent lipid peroxides [127]
Summary
Peroxisomes are ubiquitous single membrane-bound organelles that play essential roles in cellular metabolism. Peroxisomes can communicate with other organelles through membrane contact sites, peroxisome-derived metabolites, as well as retrograde signaling. It remains largely unclear how peroxisomal stress response pathways are activated and how they protect cells from damages. Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important areas of peroxisome research because of their vital role in cellular homeostasis, aging, and aging-related diseases [11,12,13,14]. We summarize recent studies on the major cellular responses induced by peroxisomal dysfunction and the role of inter-organelle crosstalk in maintaining cellular homeostasis and organelle functions. We discuss the potential roles of peroxisomes in aging and aging-related diseases
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