Curr Opin Chem Biol
February 2024
Hydrogen peroxide (HO), a natural metabolite commonly found in aerobic organisms, plays a crucial role in numerous cellular signaling processes. One of the key organelles involved in the cell's metabolism of HO is the peroxisome. In this review, we first provide a concise overview of the current understanding of HO as a molecular messenger in thiol redox signaling, along with the role of peroxisomes as guardians and modulators of cellular HO balance.
View Article and Find Full Text PDFDespite the crucial role of peroxisomes in cellular redox maintenance, little is known about how these organelles transport redox metabolites across their membrane. In this study, we sought to assess potential associations between the cellular redox landscape and the human peroxisomal solute carrier SLC25A17, also known as PMP34. This carrier has been reported to function as a counter-exchanger of adenine-containing cofactors such as coenzyme A (CoA), dephospho-CoA, flavin adenine dinucleotide, nicotinamide adenine dinucleotide (NAD), adenosine 3',5'-diphosphate, flavin mononucleotide, and adenosine monophosphate.
View Article and Find Full Text PDFPeroxisomes serve as important centers for cellular redox metabolism and communication. However, fundamental gaps remain in our understanding of how the peroxisomal redox equilibrium is maintained. In particular, very little is known about the function of the nonenzymatic antioxidant glutathione in the peroxisome interior and how the glutathione antioxidant system balances with peroxisomal protein thiols.
View Article and Find Full Text PDFPeroxisomes are functionally specialized organelles that harbor multiple hydrogen peroxide (HO)-producing and -degrading enzymes. Given that this oxidant functions as a major redox signaling agent, peroxisomes have the intrinsic ability to mediate and modulate HO-driven processes, including autophagy. However, it remains unclear whether changes in peroxisomal HO (po-HO) emission impact the autophagic process and to which extent peroxisomes with a disturbed HO metabolism are selectively eliminated through a process called "pexophagy".
View Article and Find Full Text PDFThe pyridine nucleotides NAD(H) and NADP(H) are key molecules in cellular metabolism, and measuring their levels and oxidation states with spatiotemporal precision is of great value in biomedical research. Traditional methods to assess the redox state of these metabolites are intrusive and prohibit live-cell quantifications. This obstacle was surpassed by the development of genetically encoded fluorescent biosensors enabling dynamic measurements with subcellular resolution in living cells.
View Article and Find Full Text PDFAs the reversible oxidation of protein cysteine thiols is an important mechanism in signal transduction, it is essential to have access to experimental approaches that allow for spatiotemporal indexing of the cellular sulfenome in response to local changes in HO levels. Here, we provide a step-by-step guide for enriching and identifying the sulfenome of mammalian cells at the subcellular level in response to peroxisome-derived HO by the combined use of (i) a previously developed cell line in which peroxisomal HO production can be induced in a time- and dose-dependent manner; (ii) YAP1C, a genetically encoded yeast AP-1-like transcription factor-based probe that specifically reacts with S-sulfenylated cysteines and traps them through mixed disulfide bonds; and (iii) mass spectrometry. Given that this approach includes differential labeling of reduced and reversibly oxidized cysteine residues, it can also provide additional information on the positions of the modified cysteines.
View Article and Find Full Text PDFThe involvement of peroxisomes in cellular hydrogen peroxide (HO) metabolism has been a central theme since their first biochemical characterization by Christian de Duve in 1965. While the role of HO substantially changed from an exclusively toxic molecule to a signaling messenger, the regulatory role of peroxisomes in these signaling events is still largely underappreciated. This is mainly because the number of known protein targets of peroxisome-derived HO is rather limited and testing of specific targets is predominantly based on knowledge previously gathered in related fields of research.
View Article and Find Full Text PDFPeroxisomes harbor numerous enzymes that can produce or degrade hydrogen peroxide (HO). Depending on its local concentration and environment, this oxidant can function as a redox signaling molecule or cause stochastic oxidative damage. Currently, it is well-accepted that dysfunctional peroxisomes are selectively removed by the autophagy-lysosome pathway.
View Article and Find Full Text PDFThe calcineurin inhibitors (CNI) cyclosporine A and tacrolimus comprise the basis of immunosuppressive regimes in all solid organ transplantation. However, long-term or high exposure to CNI leads to histological and functional renal damage (CNI-associated nephrotoxicity). In the kidney, proximal tubule cells are the only cells that metabolize CNI and these cells are believed to play a central role in the origin of the toxicity for this class of drugs, although the underlying mechanisms are not clear.
View Article and Find Full Text PDFPeroxisomes are multifunctional organelles best known for their role in cellular lipid and hydrogen peroxide metabolism. In this chapter, we review and discuss the diverse functions of this organelle in brain physiology and neurodegeneration, with a particular focus on oxidative stress. We first briefly summarize what is known about the various nexuses among peroxisomes, the central nervous system, oxidative stress, and neurodegenerative disease.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Res
July 2020
Peroxisomes are highly dynamic subcellular compartments with important functions in lipid and ROS metabolism. Impaired peroxisomal function can lead to severe metabolic disorders with developmental defects and neurological abnormalities. Recently, a new group of disorders has been identified, characterised by defects in the membrane dynamics and division of peroxisomes rather than by loss of metabolic functions.
View Article and Find Full Text PDFHydrogen peroxide (HO), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipid metabolism, also serve as hubs in the HO signaling network.
View Article and Find Full Text PDFPeroxisomes have the intrinsic ability to produce and scavenge hydrogen peroxide (HO), a diffusible second messenger that controls diverse cellular processes by modulating protein activity through cysteine oxidation. Current evidence indicates that HO, a molecule whose physicochemical properties are similar to those of water, traverses cellular membranes through specific aquaporin channels, called peroxiporins. Until now, no peroxiporin-like proteins have been identified in the peroxisomal membrane, and it is widely assumed that small molecules such as HO can freely permeate this membrane through PXMP2, a non-selective pore-forming protein with an upper molecular size limit of 300-600 Da.
View Article and Find Full Text PDFDisturbances in cellular redox balance have been associated with pro-aging mechanisms and increased risk for various chronic disease states. Multiple lines of evidence indicate that peroxisomes are central players in cellular redox metabolism. Nevertheless, the potential role of this organelle as intracellular redox signaling platform has been largely overlooked for a long time.
View Article and Find Full Text PDFAntioxid Redox Signal
January 2019
Significance: Peroxisomes are organelles that are best known for their role in cellular lipid and hydrogen peroxide (HO) metabolism. Emerging evidence suggests that these organelles serve as guardians and modulators of cellular redox balance, and that alterations in their redox metabolism may contribute to aging and the development of chronic diseases such as neurodegeneration, diabetes, and cancer. Recent Advances: HO is an important signaling messenger that controls many cellular processes by modulating protein activity through cysteine oxidation.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Res
October 2017
Accumulating evidence indicates that peroxisome functioning, catalase localization, and cellular oxidative balance are intimately interconnected. Nevertheless, it remains largely unclear why modest increases in the cellular redox state especially interfere with the subcellular localization of catalase, the most abundant peroxisomal antioxidant enzyme. This study aimed at gaining more insight into this phenomenon.
View Article and Find Full Text PDFAims: Peroxisomes are ubiquitous, single-membrane-bounded organelles that contain considerable amounts of enzymes involved in the production or breakdown of hydrogen peroxide (HO), a key signaling molecule in multiple biological processes and disease states. Despite this, the role of this organelle in cross-compartmental HO signaling remains largely unclear, mainly because of the difficulty to modulate peroxisomal HO production in a selective manner. This study aimed at establishing and validating a cellular model suitable to decipher the complex signaling processes associated with peroxisomal HO release.
View Article and Find Full Text PDFOver the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles.
View Article and Find Full Text PDFTo gain additional insight into how specific cell organelles may participate in redox signaling, it is essential to have access to tools and methodologies that are suitable to monitor spatiotemporal differences in the levels of different reactive oxygen species (ROS) and the oxidation state of specific redox couples. Over the years, the use of genetically encoded fluorescent redox indicators with a ratiometric readout has constantly gained in popularity because they can easily be targeted to various subcellular compartments and monitored in real time in single cells. Here we provide step-by-step protocols and tips for the successful use of roGFP2, a redox-sensitive variant of the enhanced green fluorescent protein, to monitor changes in glutathione redox balance and hydrogen peroxide homeostasis in the cytosol, peroxisomes, and mitochondria of mammalian cells.
View Article and Find Full Text PDFThe initiation and progression of many human diseases are mediated by a complex interplay of genetic, epigenetic, and environmental factors. As all diseases begin with an imbalance at the cellular level, it is essential to understand how various types of molecular aberrations, metabolic changes, and environmental stressors function as switching points in essential communication networks. In recent years, peroxisomes have emerged as important intracellular hubs for redox-, lipid-, inflammatory-, and nucleic acid-mediated signaling pathways.
View Article and Find Full Text PDFPeroxisomes are ubiquitous cell organelles essential for human health. To maintain a healthy cellular environment, dysfunctional and superfluous peroxisomes need to be selectively removed. Although emerging evidence suggests that peroxisomes are mainly degraded by pexophagy, little is known about the triggers and molecular mechanisms underlying this process in mammalian cells.
View Article and Find Full Text PDFReduction-oxidation or "redox" reactions are an integral part of a broad range of cellular processes such as gene expression, energy metabolism, protein import and folding, and autophagy. As many of these processes are intimately linked with cell fate decisions, transient or chronic changes in cellular redox equilibrium are likely to contribute to the initiation and progression of a plethora of human diseases. Since a long time, it is known that mitochondria are major players in redox regulation and signaling.
View Article and Find Full Text PDFPeroxisomal matrix proteins are synthesized on cytosolic ribosomes and transported by the shuttling receptor PEX5 to the peroxisomal membrane docking/translocation machinery, where they are translocated into the organelle matrix. Under certain experimental conditions this protein import machinery has the remarkable capacity to accept already oligomerized proteins, a property that has heavily influenced current models on the mechanism of peroxisomal protein import. However, whether or not oligomeric proteins are really the best and most frequent clients of this machinery remain unclear.
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