Article

Pexophagy: The Selective Degradation of Peroxisomes

Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0322, USA.
International Journal of Cell Biology 03/2012; 2012:512721. DOI: 10.1155/2012/512721
Source: PubMed

ABSTRACT Peroxisomes are single-membrane-bounded organelles present in the majority of eukaryotic cells. Despite the existence of great diversity among different species, cell types, and under different environmental conditions, peroxisomes contain enzymes involved in β-oxidation of fatty acids and the generation, as well as detoxification, of hydrogen peroxide. The exigency of all eukaryotic cells to quickly adapt to different environmental factors requires the ability to precisely and efficiently control peroxisome number and functionality. Peroxisome homeostasis is achieved by the counterbalance between organelle biogenesis and degradation. The selective degradation of superfluous or damaged peroxisomes is facilitated by several tightly regulated pathways. The most prominent peroxisome degradation system uses components of the general autophagy core machinery and is therefore referred to as "pexophagy." In this paper we focus on recent developments in pexophagy and provide an overview of current knowledge and future challenges in the field. We compare different modes of pexophagy and mention shared and distinct features of pexophagy in yeast model systems, mammalian cells, and other organisms.

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Available from: Andreas Till, Aug 15, 2015
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    • "In this process, numerous new organelles are produced from pre-existing peroxisomes. When fatty acids are depleted from the medium, or after re-introduction of glucose, peroxisomes are degraded via the vacuole by pexophagy [5]. Pex11 is the peroxin (i.e. a protein involved in biogenesis or organization of peroxisomes) whose activity is required for the tubulation and fission of the single peroxisomal membrane during peroxisome proliferation. "
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    ABSTRACT: Pex11 is a peroxin that regulates the number of peroxisomes in eukaryotic cells. Recently it was found that a mutation in one of the three mammalian paralogs, PEX11β, results in a neurological disorder. The molecular function of Pex11, however, is not known. Saccharomyces cerevisiae Pex11 has been shown to recruit to peroxisomes the mitochondrial fission machinery, thus enabling proliferation of peroxisomes. This process is essential for efficient fatty acid β-oxidation. In this study, we used high-content microscopy on a genome-wide scale to determine the subcellular localization pattern of yeast Pex11 in all non-essential gene deletion mutants, and in temperature sensitive essential gene mutants. Pex11 localization and morphology of peroxisomes was profoundly affected by mutations in 104 different genes that were functionally classified. A group of genes encompassing MDM10, MDM12 and MDM34 that encode the mitochondrial and cytosolic components of the ERMES complex was analyzed in greater detail. Deletion of these genes caused a specifically altered Pex11 localization pattern, whereas deletion of MMM1, the gene encoding the fourth, endoplasmic reticulum-associated component of the complex, did not result in an altered Pex11 localization or peroxisome morphology phenotype. Moreover, we found that Pex11 and Mdm34 physically interact and that Pex11 plays a role in establishing the contact sites between peroxisomes and mitochondria through the ERMES complex. Based on these results we propose that the mitochondrial/cytosolic components of the ERMES complex establish a direct interaction between mitochondria and peroxisomes through Pex11. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular Biology 03/2015; 14(11). DOI:10.1016/j.jmb.2015.03.004 · 4.33 Impact Factor
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    • "Peroxisomes are ubiquitous organelles that play an essential role in the metabolism of lipids and reactive oxygen species (Wanders et al., 2010; Titorenko and Terlecky, 2011). Peroxisome homeostasis is achieved by balancing peroxisome proliferation and pexophagy (Schrader et al., 2012; Till et al., 2012). Even mild defects in peroxisome proliferation cause pathological conditions commonly referred to as peroxisome biogenesis disorders (PBDs; Ebberink et al., 2010, 2012). "
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    ABSTRACT: Autophagy is a membrane trafficking pathway that sequesters proteins and organelles into autophagosomes. The selectivity of this pathway is determined by autophagy receptors, such as the Pichia pastoris autophagy-related protein 30 (Atg30), which controls the selective autophagy of peroxisomes (pexophagy) through the assembly of a receptor protein complex (RPC). However, how the pexophagic RPC is regulated for efficient formation of the phagophore, an isolation membrane that sequesters the peroxisome from the cytosol, is unknown. Here we describe a new, conserved acyl-CoA-binding protein, Atg37, that is an integral peroxisomal membrane protein required specifically for pexophagy at the stage of phagophore formation. Atg30 recruits Atg37 to the pexophagic RPC, where Atg37 regulates the recruitment of the scaffold protein, Atg11. Palmitoyl-CoA competes with Atg30 for Atg37 binding. The human orthologue of Atg37, acyl-CoA-binding domain containing protein 5 (ACBD5), is also peroxisomal and is required specifically for pexophagy. We suggest that Atg37/ACBD5 is a new component and positive regulator of the pexophagic RPC.
    The Journal of Cell Biology 02/2014; 204(4):541-57. DOI:10.1083/jcb.201307050 · 9.69 Impact Factor
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    • "For instance, depolarized mitochondria can be specifically recognized as autophagic substrates via a signal transduction cascade that involves the ubiquitin ligase parkin and the serine protease PTEN induced putative kinase 1 (PINK1) [3], two proteins that are frequently mutated in subjects affected by familiar variants of Parkinson's disease. Along the lines of " mitophagy " , that is, the selective autophagic removal of mitochondria , endoplasmic reticulum-, ribosome-, peroxisome-as well as pathogen-specific instances of autophagy have been described and referred to as " reticulophagy " , " ribophagy " , " pexophagy " and " xenophagy " , respectively [31] [32] [33]. In addition, stimuli that were long thought to induce an unspecific autophagic response have recently been shown to activate autophagy in a way more specific fashion. "
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    ABSTRACT: Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-κB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors.
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