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International Journal of Molecular... Jul 2020Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through... (Review)
Review
Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through division of pre-existing organelles. Studies on yeast, mammalian cells, and unicellular algae have led to a surprising finding that mitochondria and peroxisomes share the components of their division machineries. At the heart of the mitochondrial and peroxisomal division machineries is a GTPase dynamin-like protein, Dnm1/Drp1, which forms a contractile ring around the neck of the dividing organelles. During division, Dnm1/Drp1 functions as a motor protein and constricts the membrane. This mechanochemical work is achieved by utilizing energy from GTP hydrolysis. Over the last two decades, studies have focused on the structure and assembly of Dnm1/Drp1 molecules around the neck. However, the regulation of GTP during the division of mitochondrion and peroxisome is not well understood. Here, we review the current understanding of Dnm1/Drp1-mediated divisions of mitochondria and peroxisomes, exploring the mechanisms of GTP regulation during the Dnm1/Drp1 function, and provide new perspectives on their potential contribution to mitochondrial and peroxisomal biogenesis.
Topics: Animals; Cell Division; Dynamins; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Molecular Motor Proteins; Peroxisomes; Saccharomyces cerevisiae Proteins
PubMed: 32751702
DOI: 10.3390/ijms21155452 -
Oncogene Feb 2024Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed...
Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. However, the precise mechanisms controlling LD accumulation and utilization in prostate cancer are not well known. Here, we show peroxisome proliferator-activated receptor α (PPARα) acts downstream of PIM1 kinase to accelerate LD accumulation and promote cell proliferation in prostate cancer. Mechanistically, PIM1 inactivates glycogen synthase kinase 3 beta (GSK3β) via serine 9 phosphorylation. GSK3β inhibition stabilizes PPARα and enhances the transcription of genes linked to peroxisomal biogenesis (PEX3 and PEX5) and LD growth (Tip47). The effects of PIM1 on LD accumulation are abrogated with GW6471, a specific inhibitor for PPARα. Notably, LD accumulation downstream of PIM1 provides a significant survival advantage for prostate cancer cells during nutrient stress, such as glucose depletion. Inhibiting PIM reduces LD accumulation in vivo alongside slow tumor growth and proliferation. Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3β-PPARα signaling axis to promote cell proliferation and survival during nutrient stress.
Topics: Male; Humans; Animals; Mice; Glycogen Synthase Kinase 3 beta; Lipid Droplets; PPAR alpha; Prostatic Neoplasms; Cell Proliferation; Proto-Oncogene Proteins c-pim-1
PubMed: 38097734
DOI: 10.1038/s41388-023-02914-0 -
IUBMB Life Nov 2011This review summarizes the historical aspects of the study of peroxisome degradation in mammalian cells. Peroxisomes have diverse metabolic roles in response to... (Review)
Review
This review summarizes the historical aspects of the study of peroxisome degradation in mammalian cells. Peroxisomes have diverse metabolic roles in response to environmental changes and are degraded in a preferential manner, by comparison with cytosolic proteins. This review introduces three hypotheses on the degradation mechanisms: (a) the action of the peroxisome-specific Lon protease; (b) the membrane disruption effect of 15-lipoxygenase; and (c) autophagy that sequesters and degrades the organelles by lysosomal enzymes. Among these hypotheses, autophagy is now recognized as the most important mechanism for excess peroxisome degradation. One of the most striking characteristics of peroxisomes is that they are markedly proliferated in the liver by the administration of hypolipidemic drugs and industrial plasticizers. The effects of these substances were fully reversed after withdrawal of the substances, and most of the excess peroxisomes were selectively degraded and recovered to a normal number and size. Autophagic degradation of peroxisomes has been examined using this characteristic phenomenon. Excessive peroxisome degradation that occurs after cessation of hypolipidemic drugs has been extensively investigated biochemically and morphologically. The evidence shows that the degradation of excess peroxisomes and peroxisomal enzymes is inhibited by 3-methyladenine (3-MA), a specific inhibitor of autophagy. Furthermore, in liver-specific autophagy-deficient mice, rapid removal of peroxisomes was exclusively impaired, and degradation of peroxisomal enzymes was not detected. Thus, the significant contribution of autophagic machinery to peroxisomal degradation in mammals was confirmed. However, the important question of the mechanism for the selective recognition of peroxisomes by autophagosomes remains to be fully elucidated.
Topics: Animals; Arachidonate 15-Lipoxygenase; Autophagy; Cells, Cultured; Half-Life; Humans; Hypolipidemic Agents; Leupeptins; Mammals; Peroxisomes; Protease La; Ubiquitination
PubMed: 21990012
DOI: 10.1002/iub.537 -
Environmental Health Perspectives Jun 1991Peroxisome proliferators are hepatocarcinogens in rats and mice. Chronic administration of these compounds results in the development of altered areas and neoplastic... (Review)
Review
Peroxisome proliferators are hepatocarcinogens in rats and mice. Chronic administration of these compounds results in the development of altered areas and neoplastic nodules followed by hepatocellular carcinomas. All three types of hepatic lesions do not express gamma-glutamyltranspeptidase, glutathione 8-transferase-P, and alpha-fetoprotein and are resistant to iron accumulation after overload. The mechanism by which nongenotoxic peroxisome proliferators induce hepatic tumors is not well understood. It has been proposed that with continuous administration of peroxisome proliferators, liver cells are subjected to persistent oxidative stress resulting from marked proliferation of peroxisomes and a differential increase in the levels of H2O2 producing (20- to 30-fold) and degrading (2-fold) enzymes. Free oxygen radicals lead to DNA damage (both directly and through lipid peroxidation) and thus may cause initiation and promotion of the carcinogenic process.
Topics: Animals; Carcinogens; Free Radicals; Glutathione Transferase; Herbicides; Hypertrophy; Hypolipidemic Agents; Liver; Liver Neoplasms, Experimental; Mice; Microbodies; Nafenopin; Neoplasm Proteins; Oxidation-Reduction; Oxygen; Phthalic Acids; Plasticizers; Rats; Trichloroethylene; gamma-Glutamyltransferase
PubMed: 1685443
DOI: 10.1289/ehp.9193205 -
Experimental Physiology Jan 2008Epoxygenases, particularly of the CYP2C and CYP2J families, are important lipid-metabolizing enzymes. Epoxygenases are found throughout the cardiovascular system where... (Review)
Review
Epoxygenases, particularly of the CYP2C and CYP2J families, are important lipid-metabolizing enzymes. Epoxygenases are found throughout the cardiovascular system where their lipid products, particularly the epoxyeicosatrienoic acids (EETs), which are arachidonic acid metabolites, have the potential to regulate vascular tone, cellular proliferation, migration, inflammation and cardiac function. The receptors for EETs are, however, poorly understood. The peroxisome proliferator-activated receptors (PPARs) are a family of three (alpha, beta/delta and gamma) nuclear receptors that are activated by lipid metabolites. Activation of PPAR alpha and PPAR gamma, similar to the longer term effects of EETs, causes the inhibition of vascular cell proliferation, migration and inflammation. Interestingly, EETs and their metabolites have recently been found to active both PPAR alpha and PPAR gamma. The epoxygenase-EET-PPAR pathway may therefore represent a novel endogenous protective pathway by which short-lived lipid mediators control vascular cell activation.
Topics: Animals; Blood Vessels; Cell Movement; Cell Proliferation; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Eicosanoic Acids; Heart; Humans; Inflammation; Mammals; Muscle Tonus; Muscle, Smooth, Vascular; Oxygenases; Peroxisome Proliferator-Activated Receptors
PubMed: 17872966
DOI: 10.1113/expphysiol.2007.038612 -
Biochimica Et Biophysica Acta Dec 2006Unicellular organisms such as yeast constantly monitor their environment and respond to nutritional cues. Rapid adaptation to ambient changes may include modification... (Review)
Review
Unicellular organisms such as yeast constantly monitor their environment and respond to nutritional cues. Rapid adaptation to ambient changes may include modification and degradation of proteins; alterations in mRNA stability; and differential rates of translation. However, for a more prolonged response, changes are initiated in the expression of genes involved in the utilization of energy sources whose availability constantly fluctuates. For example, in the presence of oleic acid as a sole carbon source, yeast cells induce the expression of a discrete set of enzymes for fatty acid beta-oxidation as well as proteins involved in the expansion of the peroxisomal compartment containing this process. In this review chapter, we discuss the factors regulating oleate induction in Saccharomyces cerevisiae, and we also deal with peroxisome proliferation in other organisms, briefly mentioning fatty acid-independent signals that can trigger this process.
Topics: Animals; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Glucose; Ligands; Mitosporic Fungi; Oleic Acids; Peroxisomes; Pichia; Protein Conformation; Protein Serine-Threonine Kinases; Response Elements; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors; Transcription, Genetic; Up-Regulation
PubMed: 16949166
DOI: 10.1016/j.bbamcr.2006.07.011 -
Journal of Cellular and Molecular... 2003Peroxisomes are metabolic organelles with enzymatic content that are found in virtually all cells and are involved in beta-oxidation of fatty acids, hydrogen... (Review)
Review
Peroxisomes are metabolic organelles with enzymatic content that are found in virtually all cells and are involved in beta-oxidation of fatty acids, hydrogen peroxide-based respiration and defence against oxidative stress. The steps of their biogenesis involves "peroxins", proteins encoded by PEX genes. Peroxins are involved in three key stages of peroxisome development: (1). import of peroxisomal membrane proteins; (2). import of peroxisomal matrix proteins and (3). peroxisome proliferation. Of these three areas, peroxisomal matrix-protein import is by far the best understood and accounts for most of the available published data on peroxisome biogenesis. Defects in peroxisome biogenesis result in peroxisome biogenesis disorders (PBDs), which although rare, have no known cure to-date. This review explores current understanding of each key area in peroxisome biogenesis, paying particular attention to the role of protein import.
Topics: Animals; Biological Transport, Active; Humans; Membrane Proteins; Peroxisomes; Plants; Proteins; Saccharomyces cerevisiae
PubMed: 14754507
DOI: 10.1111/j.1582-4934.2003.tb00241.x -
ELife Apr 2022How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and...
How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH-shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Δgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2, and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol, and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.
Topics: Adenosine Triphosphate; Cell Proliferation; Genes, Fungal; Humans; Methanol; Mitochondrial Diseases; NAD; Oxidative Phosphorylation; Peroxisomes; Protein Serine-Threonine Kinases; Repressor Proteins; Saccharomycetales; Signal Transduction
PubMed: 35467529
DOI: 10.7554/eLife.75143 -
Traffic (Copenhagen, Denmark) Feb 2010Peroxisomes are unique organelles which display properties of autonomous organelles, as they can multiply by fission of pre-existing ones. Peroxisomes, however, can also... (Review)
Review
Peroxisomes are unique organelles which display properties of autonomous organelles, as they can multiply by fission of pre-existing ones. Peroxisomes, however, can also develop from the endoplasmic reticulum (ER). This process has convincingly been shown in peroxisome-deficient yeast cells, upon reintroduction of the corresponding gene. Whether peroxisomes also are formed from the ER in wild-type cells that contain peroxisomes is still under debate. Also, the existence of vesicular transport pathways between peroxisomes and the ER is still unresolved. Several new proteins and pathways that play a role in peroxisome proliferation have been identified in the last few years. A surprising finding was that proteins well known for their function in mitochondrial fission (Fis1, Dnm1) are responsible for peroxisome fission as well. In this contribution we discuss recent advancements in research on peroxisome proliferation.
Topics: Animals; Endoplasmic Reticulum; Humans; Models, Biological; Peroxisomes
PubMed: 20015113
DOI: 10.1111/j.1600-0854.2009.01019.x -
IUBMB Life Sep 2009The endoplasmic reticulum (ER) response has been thought a cytoprotective mechanism to cope with accumulation of unfolded proteins in the ER. Recent progress has made a... (Review)
Review
The endoplasmic reticulum (ER) response has been thought a cytoprotective mechanism to cope with accumulation of unfolded proteins in the ER. Recent progress has made a quantum leap revealing that ER stress response can be regarded as an autoregulatory system adjusting the ER capacity to cellular demand. This Copernican change raised a novel fundamental question in cell biology: how do cells regulate the capacity of each organelle in accordance with cellular needs? Although this fundamental question has not been fully addressed yet, research about each organelle has been advancing. The proliferation of the peroxisome is regulated by the PPAR alpha pathway, whereas the abundance of mitochondria appears to be regulated by mitochondrial retrograde signaling and the mitochondrial unfolded protein response. The functional capacity of the Golgi apparatus may be regulated by the mechanism of the Golgi stress response. These observations strongly suggest the existence of an elaborate network of organelle autoregulation in eukaryotic cells.
Topics: Endoplasmic Reticulum; Golgi Apparatus; Mitochondria; Peroxisomes; Protein Denaturation; Signal Transduction
PubMed: 19504573
DOI: 10.1002/iub.229