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The Journal of Cell Biology May 2021Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In...
Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and that functions, partially redundantly with Vps13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro was linked to mitochondrial dynamics but not to lipid transport. Here we show that Miro, including its peroxisome-enriched splice variant, recruits the lipid transport protein VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson's disease pathogenesis.
Topics: Animals; Biological Transport; COS Cells; Cell Line; Cell Line, Tumor; Chlorocebus aethiops; Endoplasmic Reticulum; Eukaryota; GTP Phosphohydrolases; HeLa Cells; Humans; Mitochondria; Mitochondrial Dynamics; Parkinson Disease; Peroxisomes; Proteins; Ubiquitin-Protein Ligases
PubMed: 33891013
DOI: 10.1083/jcb.202010004 -
Molecular Cell Sep 2022Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which...
Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which interacts with a docking complex in the peroxisomal membrane and then returns to the cytosol after monoubiquitination by a membrane-embedded ubiquitin ligase. The mechanism by which PEX5 shuttles between cytosol and peroxisomes and releases cargo inside the lumen is unclear. Here, we use Xenopus egg extract to demonstrate that PEX5 accompanies cargo completely into the lumen, utilizing WxxxF/Y motifs near its N terminus that bind a lumenal domain of the docking complex. PEX5 recycling is initiated by an amphipathic helix that binds to the lumenal side of the ubiquitin ligase. The N terminus then emerges in the cytosol for monoubiquitination. Finally, PEX5 is extracted from the lumen, resulting in the unfolding of the receptor and cargo release. Our results reveal the unique mechanism by which PEX5 ferries proteins into peroxisomes.
Topics: Carrier Proteins; Humans; Ligases; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Protein Transport; Receptors, Cytoplasmic and Nuclear; Ubiquitin
PubMed: 35931083
DOI: 10.1016/j.molcel.2022.07.004 -
Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network.Nature Cell Biology Jan 2024The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of...
The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism disrupt mitochondrial structure and function. Our quantitative total-organelle profiling approach for focussed ion beam scanning electron microscopy revealed in unprecedented detail that specific organelle dysfunctions precipitate multi-organelle biogenesis defects, impair mitochondrial morphology and reduce respiration. Multi-omics profiling showed a unified proteome response and global shifts in lipid and glycoprotein homeostasis that are elicited when organelle biogenesis is compromised, and that the resulting mitochondrial dysfunction can be rescued with precursors for ether-glycerophospholipid metabolic pathways. This work defines metabolic and morphological interactions between organelles and how their perturbation can cause disease.
Topics: Organelle Biogenesis; Organelles; Peroxisomes; Golgi Apparatus; Mitochondria; Lipids
PubMed: 38129691
DOI: 10.1038/s41556-023-01297-4 -
The Journal of Cell Biology Dec 2023Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses....
Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses. However, the cellular mechanisms by which peroxisomes contribute to bacterial elimination in macrophages remain elusive. Here, we investigated peroxisome function in iPSC-derived human macrophages (iPSDM) during infection with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered peroxisome biogenesis requires the ESX-1 type 7 secretion system, critical for cytosolic access. iPSDM lacking peroxisomes were permissive to Mtb wild-type (WT) replication but were able to restrict an Mtb mutant missing functional ESX-1, suggesting a role for peroxisomes in the control of cytosolic but not phagosomal Mtb. Using genetically encoded localization-dependent ROS probes, we found peroxisomes increased ROS levels during Mtb WT infection. Thus, human macrophages respond to the infection by increasing peroxisomes that generate ROS primarily to restrict cytosolic Mtb. Our data uncover a peroxisome-controlled, ROS-mediated mechanism that contributes to the restriction of cytosolic bacteria.
Topics: Humans; Cytosol; Macrophages; Mycobacterium tuberculosis; Peroxisomes; Reactive Oxygen Species; Type VII Secretion Systems
PubMed: 37737955
DOI: 10.1083/jcb.202303066 -
Cells Sep 2022Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely...
Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely unknown. In this study, we identified several BRD4 inhibitors, including molibresib, a novel pexophagy inducer, via chemical library screening. Treatment with molibresib promotes loss of peroxisomes selectively, but not mitochondria, ER, or Golgi apparatus in HeLa cells. Consistently, depletion of BRD4 expression also induced pexophagy in RPE cells. In addition, the inhibition of BRD4 by molibresib increased autophagic degradation of peroxisome ATG7-dependency. We further found that molibresib produced reactive oxygen species (ROS), which potentiates ATM activation. Inhibition of ROS or ATM suppressed the loss of peroxisomes in molibresib-treated cells. Taken together, our data suggest that inhibition of BRD4 promotes pexophagy by increasing ROS and ATM activation.
Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; HeLa Cells; Humans; Macroautophagy; Nuclear Proteins; Peroxisomes; Reactive Oxygen Species; Transcription Factors
PubMed: 36139416
DOI: 10.3390/cells11182839 -
Annual Review of Cell and Developmental... Oct 2019Macroautophagy is an intracellular degradation system that delivers diverse cytoplasmic materials to lysosomes via autophagosomes. Recent advances have enabled... (Review)
Review
Macroautophagy is an intracellular degradation system that delivers diverse cytoplasmic materials to lysosomes via autophagosomes. Recent advances have enabled identification of several selective autophagy substrates and receptors, greatly expanding our understanding of the cellular functions of autophagy. In this review, we describe the diverse cellular functions of macroautophagy, including its essential contribution to metabolic adaptation and cellular homeostasis. We also discuss emerging findings on the mechanisms and functions of various types of selective autophagy.
Topics: Animals; Autophagosomes; Autophagy; Endoplasmic Reticulum; Homeostasis; Humans; Lysosomes; Mitochondria; Nutrients; Peroxisomes
PubMed: 31283377
DOI: 10.1146/annurev-cellbio-100818-125300 -
International Journal of Molecular... Sep 2022Peroxisomes are a class of simple organelles that play an important role in plant reactive oxygen species (ROS) metabolism. Experimental evidence reveals the involvement... (Review)
Review
Peroxisomes are a class of simple organelles that play an important role in plant reactive oxygen species (ROS) metabolism. Experimental evidence reveals the involvement of ROS in programmed cell death (PCD) in plants. Plant PCD is crucial for the regulation of plant growth, development and environmental stress resistance. However, it is unclear whether the ROS originated from peroxisomes participated in cellular PCD. Enzymes involved in the peroxisomal ROS metabolic pathways are key mediators to figure out the relationship between peroxisome-derived ROS and PCD. Here, we summarize the peroxisomal ROS generation and scavenging pathways and explain how peroxisome-derived ROS participate in PCD based on recent progress in the functional study of enzymes related to peroxisomal ROS generation or scavenging. We aimed to elucidate the role of the peroxisomal ROS regulatory system in cellular PCD to show its potential in terms of accurate PCD regulation, which contribute to environmental stress resistance.
Topics: Apoptosis; Metabolic Networks and Pathways; Peroxisomes; Plants; Reactive Oxygen Species
PubMed: 36077484
DOI: 10.3390/ijms231710087 -
Journal of the American Chemical Society Nov 2023Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead...
Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead to the accumulation of pathological aggregates, correlating with aging and neurodegenerative diseases. However, a broadly applicable methodology is not available for the targeted degradation of protein aggregates or organelles in mammalian cells. Herein, we developed a series of autophagy receptor-inspired targeting chimeras (AceTACs) that can induce the targeted degradation of aggregation-prone proteins and protein aggregates (e.g., huntingtin, TDP-43, and FUS mutants), as well as organelles (e.g., mitochondria, peroxisomes, and endoplasmic reticulum). These antibody-fusion-based AceTAC degraders were designed to mimic the function of autophagy receptors, simultaneously binding with the cellular targets and the LC3 proteins on the autophagosomal membrane, eventually transporting the target to the autophagy-lysosomal process for degradation. The AceTAC degradation system provides design principles for antibody-based degradation through autophagy, largely expanding the scope of intracellular targeted degradation technologies.
Topics: Animals; Protein Aggregates; Autophagy; Endoplasmic Reticulum; Lysosomes; Peroxisomes; Mammals
PubMed: 37748140
DOI: 10.1021/jacs.3c05199 -
Cells Jun 2022Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to... (Review)
Review
Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome-ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome-ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed.
Topics: Animals; GTP Phosphohydrolases; Humans; Mammals; Membrane Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Peroxisomes
PubMed: 35741050
DOI: 10.3390/cells11121922 -
Advances in Experimental Medicine and... 2020Peroxisomopathies are rare diseases due to dysfunctions of the peroxisome in which this organelle is either absent or with impaired activities. These diseases, at the... (Review)
Review
Peroxisomopathies are rare diseases due to dysfunctions of the peroxisome in which this organelle is either absent or with impaired activities. These diseases, at the exception of type I hyperoxaluria and acatalasaemia, affect the central and peripheral nervous system. Due to the significant impact of peroxisomal abnormalities on the functioning of nerve cells, this has led to an interest in peroxisome in common neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. In these diseases, a role of the peroxisome is suspected on the basis of the fatty acid and phospholipid profile in the biological fluids and the brains of patients. It is also speculated that peroxisomal dysfunctions could contribute to oxidative stress and mitochondrial alterations which are recognized as major players in the development of neurodegenerative diseases. Based on clinical and in vitro studies, the data obtained support a potential role of peroxisome in Alzheimer's disease and multiple sclerosis.
Topics: Alzheimer Disease; Humans; Multiple Sclerosis; Oxidative Stress; Peroxisomes
PubMed: 33417210
DOI: 10.1007/978-3-030-60204-8_8