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Annals of Neurology Sep 2023Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune...
OBJECTIVE
Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy.
METHODS
Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods.
RESULTS
SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11β, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05).
INTERPRETATION
COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023;94:531-546.
Topics: Animals; Humans; COVID-19; SARS-CoV-2; Neuroinflammatory Diseases; RNA, Viral; Peroxisomes; Brain
PubMed: 37190821
DOI: 10.1002/ana.26679 -
International Journal of Molecular... Jan 2020The removal of damaged or superfluous organelles from the cytosol by selective autophagy is required to maintain organelle function, quality control and overall cellular... (Review)
Review
The removal of damaged or superfluous organelles from the cytosol by selective autophagy is required to maintain organelle function, quality control and overall cellular homeostasis. Precisely how substrate selectivity is achieved, and how individual substrates are degraded during selective autophagy in response to both extracellular and intracellular cues is not well understood. The aim of this review is to highlight pexophagy, the autophagic degradation of peroxisomes, as a model for selective autophagy. Peroxisomes are dynamic organelles whose abundance is rapidly modulated in response to metabolic demands. Peroxisomes are routinely turned over by pexophagy for organelle quality control yet can also be degraded by pexophagy in response to external stimuli such as amino acid starvation or hypoxia. This review discusses the molecular machinery and regulatory mechanisms governing substrate selectivity during both quality-control pexophagy and pexophagy in response to external stimuli, in yeast and mammalian systems. We draw lessons from pexophagy to infer how the cell may coordinate the degradation of individual substrates by selective autophagy across different cellular cues.
Topics: Animals; Autophagy; Macroautophagy; Models, Theoretical; Peroxisomes
PubMed: 31963200
DOI: 10.3390/ijms21020578 -
Cells May 2021Peroxisomes play essential roles in diverse cellular metabolism functions, and their dynamic homeostasis is maintained through the coordination of peroxisome biogenesis... (Review)
Review
Peroxisomes play essential roles in diverse cellular metabolism functions, and their dynamic homeostasis is maintained through the coordination of peroxisome biogenesis and turnover. Pexophagy, selective autophagic degradation of peroxisomes, is a major mechanism for removing damaged and/or superfluous peroxisomes. Dysregulation of pexophagy impairs the physiological functions of peroxisomes and contributes to the progression of many human diseases. However, the mechanisms and functions of pexophagy in mammalian cells remain largely unknown compared to those in yeast. This review focuses on mammalian pexophagy and aims to advance the understanding of the roles of pexophagy in human health and diseases. Increasing evidence shows that ubiquitination can serve as a signal for pexophagy, and ubiquitin-binding receptors, substrates, and E3 ligases/deubiquitinases involved in pexophagy have been described. Alternatively, pexophagy can be achieved in a ubiquitin-independent manner. We discuss the mechanisms of these ubiquitin-dependent and ubiquitin-independent pexophagy pathways and summarize several inducible conditions currently used to study pexophagy. We highlight several roles of pexophagy in human health and how its dysregulation may contribute to diseases.
Topics: Animals; Humans; Macroautophagy; Peroxisomes; Signal Transduction; Ubiquitination
PubMed: 34063724
DOI: 10.3390/cells10051094 -
Journal of Cell Science Jun 2023Membrane contact sites are defined as regions of close proximity between two membranes; this association is mediated by protein-protein and/or protein-lipid... (Review)
Review
Membrane contact sites are defined as regions of close proximity between two membranes; this association is mediated by protein-protein and/or protein-lipid interactions. Contact sites are often involved in lipid transport, but also can perform other functions. Peroxisomal membrane contact sites have obtained little attention compared to those of other cell organelles. However, recent studies resulted in a big leap in our knowledge of the occurrence, composition and function of peroxisomal contact sites. Studies in yeast strongly contributed to this progress. In this Review, we present an overview of our current knowledge on peroxisomal membrane contact sites in various yeast species, including Hansenula polymorpha, Saccharomyces cerevisiae, Pichia pastoris and Yarrowia lipolytica. Yeast peroxisomes form contacts with almost all other cellular organelles and with the plasma membrane. The absence of a component of a yeast peroxisomal contact site complex results in a range of peroxisomal phenotypes, including metabolic and biogenesis defects and alterations in organelle number, size or position.
Topics: Saccharomyces cerevisiae; Peroxisomes; Mitochondrial Membranes; Biological Transport; Lipids; Fungal Proteins; Saccharomyces cerevisiae Proteins
PubMed: 37288671
DOI: 10.1242/jcs.259440 -
Biochimica Et Biophysica Acta.... Feb 2020The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing... (Review)
Review
The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing the side chains of all conserved residues to the same side. PTS2 motifs are recognized by a bipartite protein complex consisting of the receptor PEX7 and a co-receptor. Cargo-loaded receptor complexes are translocated across the peroxisomal membrane by a transient pore and inside peroxisomes, cargo proteins are released and processed in many, but not all species. The components of the bipartite receptor are re-exported into the cytosol by a ubiquitin-mediated and ATP-driven export mechanism. Structurally, PTS2 motifs resemble other N-terminal targeting signals, whereas the functional relation to the second peroxisomal targeting signal (PTS1) is unclear. Although only a few PTS2-carrying proteins are known in humans, subjects lacking a functional import mechanism for these proteins suffer from the severe inherited disease rhizomelic chondrodysplasia punctata.
Topics: Amino Acid Motifs; Chondrodysplasia Punctata, Rhizomelic; Humans; Membrane Proteins; Peroxisomal Targeting Signal 2 Receptor; Peroxisomes; Protein Domains; Protein Structure, Quaternary; Protein Transport
PubMed: 31751594
DOI: 10.1016/j.bbamcr.2019.118609 -
Annual Review of Analytical Chemistry... Jun 2022Cellular organelles are highly specialized compartments with distinct functions. With the increasing resolution of detection methods, it is becoming clearer that same... (Review)
Review
Cellular organelles are highly specialized compartments with distinct functions. With the increasing resolution of detection methods, it is becoming clearer that same organelles may have different functions or properties not only within different cell populations of a tissue but also within the same cell. Dysfunction or altered function affects the organelle itself and may also lead to malignancies or undesirable cell death. To understand cellular function or dysfunction, it is therefore necessary to analyze cellular components at the single-organelle level. Here, we review the recent advances in analyzing cellular function at single-organelle resolution using high-parameter flow cytometry or multicolor confocal microscopy. We focus on the analysis of mitochondria, as they are organelles at the crossroads of various cellular signaling pathways and functions. However, most of the applied methods/technologies are transferable to any other organelle, such as the endoplasmic reticulum, lysosomes, or peroxisomes.
Topics: Endoplasmic Reticulum; Lysosomes; Microscopy, Confocal; Mitochondria; Peroxisomes
PubMed: 35303775
DOI: 10.1146/annurev-anchem-061020-111722 -
Experimental & Molecular Medicine Sep 2020In recent decades, the role of the peroxisome in physiology and disease conditions has become increasingly important. Together with the mitochondria and other cellular... (Review)
Review
In recent decades, the role of the peroxisome in physiology and disease conditions has become increasingly important. Together with the mitochondria and other cellular organelles, peroxisomes support key metabolic platforms for the oxidation of various fatty acids and regulate redox conditions. In addition, peroxisomes contribute to the biosynthesis of essential lipid molecules, such as bile acid, cholesterol, docosahexaenoic acid, and plasmalogen. Therefore, the quality control mechanisms that regulate peroxisome biogenesis and degradation are important for cellular homeostasis. Current evidence indicates that peroxisomal function is often reduced or dysregulated in various human disease conditions, such as neurodegenerative diseases. Here, we review the recent progress that has been made toward understanding the quality control systems that regulate peroxisomes and their pathological implications.
Topics: Animals; Biomarkers; Disease Susceptibility; Endoplasmic Reticulum; Homeostasis; Humans; Lipid Metabolism; Metabolic Networks and Pathways; Neurodegenerative Diseases; Oxidation-Reduction; Peroxisomes; Protein Processing, Post-Translational
PubMed: 32917959
DOI: 10.1038/s12276-020-00503-9 -
Essays in Biochemistry Aug 2022Plant peroxisomes host critical metabolic reactions and insulate the rest of the cell from reactive byproducts. The specialization of peroxisomal reactions is rooted in... (Review)
Review
Plant peroxisomes host critical metabolic reactions and insulate the rest of the cell from reactive byproducts. The specialization of peroxisomal reactions is rooted in how the organelle modulates its proteome to be suitable for the tissue, environment, and developmental stage of the organism. The story of plant peroxisomal proteostasis begins with transcriptional regulation of peroxisomal protein genes and the synthesis, trafficking, import, and folding of peroxisomal proteins. The saga continues with assembly and disaggregation by chaperones and degradation via proteases or the proteasome. The story concludes with organelle recycling via autophagy. Some of these processes as well as the proteins that facilitate them are peroxisome-specific, while others are shared among organelles. Our understanding of translational regulation of plant peroxisomal protein transcripts and proteins necessary for pexophagy remain based in findings from other models. Recent strides to elucidate transcriptional control, membrane dynamics, protein trafficking, and conditions that induce peroxisome turnover have expanded our knowledge of plant peroxisomal proteostasis. Here we review our current understanding of the processes and proteins necessary for plant peroxisome proteostasis-the emergence, maintenance, and clearance of the peroxisomal proteome.
Topics: Autophagy; Peroxisomes; Protein Transport; Proteome; Proteostasis
PubMed: 35538741
DOI: 10.1042/EBC20210059 -
The Journal of Cell Biology May 2021The VPS13 gene family consists of VPS13A-D in mammals. Although all four genes have been linked to human diseases, their cellular functions are poorly understood,...
The VPS13 gene family consists of VPS13A-D in mammals. Although all four genes have been linked to human diseases, their cellular functions are poorly understood, particularly those of VPS13D. We generated and characterized knockouts of each VPS13 gene in HeLa cells. Among the individual knockouts, only VPS13D-KO cells exhibit abnormal mitochondrial morphology. Additionally, VPS13D loss leads to either partial or complete peroxisome loss in several transformed cell lines and in fibroblasts derived from a VPS13D mutation-carrying patient with recessive spinocerebellar ataxia. Our data show that VPS13D regulates peroxisome biogenesis.
Topics: HEK293 Cells; HeLa Cells; Humans; Mitochondria; Mutation; Peroxisomes; Proteins
PubMed: 33891012
DOI: 10.1083/jcb.202001188 -
Plant Physiology Apr 2021The life strategy of plants includes their ability to respond quickly at the cellular level to changes in their environment. The use of targeted fluorescent protein...
The life strategy of plants includes their ability to respond quickly at the cellular level to changes in their environment. The use of targeted fluorescent protein probes and imaging of living cells has revealed several rapidly induced organelle responses that create the efficient sub-cellular machinery for maintaining homeostasis in the plant cell. Several organelles, including plastids, mitochondria, and peroxisomes, extend and retract thin tubules that have been named stromules, matrixules, and peroxules, respectively. Here, I combine all these thin tubular forms under the common head of organelle extensions. All extensions change shape continuously and in their elongated form considerably increase organelle outreach into the surrounding cytoplasm. Their pleomorphy reflects their interactions with the dynamic endoplasmic reticulum and cytoskeletal elements. Here, using foundational images and time-lapse movies, and providing salient information on some molecular and biochemically characterized mutants with increased organelle extensions, I draw attention to their common role in maintaining homeostasis in plant cells.
Topics: Arabidopsis; Endoplasmic Reticulum; Homeostasis; Mitochondria; Peroxisomes; Plant Cells; Plastids
PubMed: 33793902
DOI: 10.1093/plphys/kiaa055