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Cell Reports Apr 2024Physiological dysfunction confers negative valence to coincidental sensory cues to induce the formation of aversive associative memory. How peripheral tissue stress...
Physiological dysfunction confers negative valence to coincidental sensory cues to induce the formation of aversive associative memory. How peripheral tissue stress engages neuromodulatory mechanisms to form aversive memory is poorly understood. Here, we show that in the nematode C. elegans, mitochondrial disruption induces aversive memory through peroxisomal β-oxidation genes in non-neural tissues, including pmp-4/very-long-chain fatty acid transporter, dhs-28/3-hydroxylacyl-CoA dehydrogenase, and daf-22/3-ketoacyl-CoA thiolase. Upregulation of peroxisomal β-oxidation genes under mitochondrial stress requires the nuclear hormone receptor NHR-49. Importantly, the memory-promoting function of peroxisomal β-oxidation is independent of its canonical role in pheromone production. Peripheral signals derived from the peroxisomes target NSM, a critical neuron for memory formation under stress, to upregulate serotonin synthesis and remodel evoked responses to sensory cues. Our genetic, transcriptomic, and metabolomic approaches establish peroxisomal lipid signaling as a crucial mechanism that connects peripheral mitochondrial stress to central serotonin neuromodulation in aversive memory formation.
Topics: Animals; Caenorhabditis elegans; Peroxisomes; Serotonin; Caenorhabditis elegans Proteins; Signal Transduction; Oxidation-Reduction; Memory; Mitochondria; Neurons; Stress, Physiological; Receptors, Cytoplasmic and Nuclear
PubMed: 38520690
DOI: 10.1016/j.celrep.2024.113996 -
Cell Reports Feb 2024Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles,...
Peroxisome biogenesis disorders (PBDs) represent a group of metabolic conditions that cause severe developmental defects. Peroxisomes are essential metabolic organelles, present in virtually every eukaryotic cell and mediating key processes in immunometabolism. To date, the full spectrum of PBDs remains to be identified, and the impact PBDs have on immune function is unexplored. This study presents a characterization of the hepatic immune compartment of a neonatal PBD mouse model at single-cell resolution to establish the importance and function of peroxisomes in developmental hematopoiesis. We report that hematopoietic defects are a feature in a severe PBD murine model. Finally, we identify a role for peroxisomes in the regulation of the major histocompatibility class II expression and antigen presentation to CD4 T cells in dendritic cells. This study adds to our understanding of the mechanisms of PBDs and expands our knowledge of the role of peroxisomes in immunometabolism.
Topics: Animals; Mice; Zellweger Syndrome; Peroxisomes; Antigen Presentation; Peroxisomal Disorders
PubMed: 38329874
DOI: 10.1016/j.celrep.2024.113744 -
MBio Aug 2023Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and...
Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and secondary metabolite biosynthesis. A suite of Pex proteins (peroxins) maintains peroxisomes, while peroxisomal matrix enzymes execute peroxisome functions. Insertional mutagenesis identified peroxin genes as essential components supporting the intraphagosomal growth of the fungal pathogen . Disruption of the peroxins Pex5, Pex10, or Pex33 in prevented peroxisome import of proteins targeted to the organelle via the PTS1 pathway. This loss of peroxisome protein import limited intracellular growth in macrophages and attenuated virulence in an acute histoplasmosis infection model. Interruption of the alternate PTS2 import pathway also attenuated virulence, although only at later time points of infection. The Sid1 and Sid3 siderophore biosynthesis proteins contain a PTS1 peroxisome import signal and localize to the peroxisome. Loss of either the PTS1 or PTS2 peroxisome import pathway impaired siderophore production and iron acquisition in , demonstrating compartmentalization of at least some biosynthetic steps for hydroxamate siderophore biosynthesis. However, the loss of PTS1-based peroxisome import caused earlier virulence attenuation than either the loss of PTS2-based protein import or the loss of siderophore biosynthesis, indicating additional PTS1-dependent peroxisomal functions are important for virulence. Furthermore, disruption of the Pex11 peroxin also attenuated virulence independently of peroxisomal protein import and siderophore biosynthesis. These findings demonstrate peroxisomes contribute to pathogenesis by facilitating siderophore biosynthesis and another unidentified role(s) for the organelle during fungal virulence. IMPORTANCE The fungal pathogen infects host phagocytes and establishes a replication-permissive niche within the cells. To do so, overcomes and subverts antifungal defense mechanisms which include the limitation of essential micronutrients. replication within host cells requires multiple distinct functions of the fungal peroxisome organelle. These peroxisomal functions contribute to pathogenesis at different times during infection and include peroxisome-dependent biosynthesis of iron-scavenging siderophores to enable fungal proliferation, particularly after activation of cell-mediated immunity. The multiple essential roles of fungal peroxisomes reveal this organelle as a potential but untapped target for the development of therapeutics.
Topics: Histoplasma; Virulence; Siderophores; Peroxins; Peroxisomes; Adaptation, Physiological
PubMed: 37432032
DOI: 10.1128/mbio.03284-22 -
PLoS Biology Feb 2024Peroxisomes are organelles with crucial functions in oxidative metabolism. To correctly target to peroxisomes, proteins require specialized targeting signals. A mystery...
Peroxisomes are organelles with crucial functions in oxidative metabolism. To correctly target to peroxisomes, proteins require specialized targeting signals. A mystery in the field is the sorting of proteins that carry a targeting signal for peroxisomes and as well as for other organelles, such as mitochondria or the endoplasmic reticulum (ER). Exploring several of these proteins in fungal model systems, we observed that they can act as tethers bridging organelles together to create contact sites. We show that in Saccharomyces cerevisiae this mode of tethering involves the peroxisome import machinery, the ER-mitochondria encounter structure (ERMES) at mitochondria and the guided entry of tail-anchored proteins (GET) pathway at the ER. Our findings introduce a previously unexplored concept of how dual affinity proteins can regulate organelle attachment and communication.
Topics: Peroxisomes; Mitochondria; Endoplasmic Reticulum; Cell Movement; Cell Respiration; Saccharomyces cerevisiae
PubMed: 38377076
DOI: 10.1371/journal.pbio.3002508 -
Frontiers in Bioscience (Landmark... Dec 2023Peroxisomes are membrane-bound organelles that contain one or more types of oxidative enzymes. Aberrant localization of peroxisomal proteins can contribute to the...
BACKGROUND
Peroxisomes are membrane-bound organelles that contain one or more types of oxidative enzymes. Aberrant localization of peroxisomal proteins can contribute to the development of various diseases. To more accurately identify and locate peroxisomal proteins, we developed the ProSE-Pero model.
METHODS
We employed three methods based on deep representation learning models to extract the characteristics of peroxisomal proteins and compared their performance. Furthermore, we used the SVMSMOTE balanced dataset, SHAP interpretation model, variance analysis (ANOVA), and light gradient boosting machine (LightGBM) to select and compare the extracted features. We also constructed several traditional machine learning methods and four deep learning models to train and test our model on a dataset of 160 peroxisomal proteins using tenfold cross-validation.
RESULTS
Our proposed ProSE-Pero model achieves high performance with a specificity (Sp) of 93.37%, a sensitivity (Sn) of 82.41%, an accuracy (Acc) of 95.77%, a Matthews correlation coefficient (MCC) of 0.8241, an F1 score of 0.8996, and an area under the curve (AUC) of 0.9818. Additionally, we extended our method to identify plant vacuole proteins and achieved an accuracy of 91.90% on the independent test set, which is approximately 5% higher than the latest iPVP-DRLF model.
CONCLUSIONS
Our model surpasses the existing In-Pero model in terms of peroxisomal protein localization and identification. Additionally, our study showcases the proficient performance of the pre-trained multitasking language model ProSE in extracting features from protein sequences. With its established validity and broad generalization, our model holds considerable potential for expanding its application to the localization and identification of proteins in other organelles, such as mitochondria and Golgi proteins, in future investigations.
Topics: Proteins; Language; Amino Acid Sequence; Peroxisomes; Machine Learning
PubMed: 38179735
DOI: 10.31083/j.fbl2812322 -
Orphanet Journal of Rare Diseases Nov 2023Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are...
BACKGROUND
Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs.
METHODS
Three patients with ZSD (2 M, 1 F; age range 8-17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy.
RESULTS
X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20-19.92) and 2.90-fold (range 1.43-4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio.
CONCLUSIONS
In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.
Topics: Humans; Child; Adolescent; Child, Preschool; Young Adult; Adult; Adrenoleukodystrophy; Zellweger Syndrome; Leukocytes, Mononuclear; Peroxisomes; Oxidation-Reduction
PubMed: 37974207
DOI: 10.1186/s13023-023-02940-x -
BMC Urology Jan 2024Kidney clear cell carcinoma (KIRC) is the most common subtype of renal cell carcinoma. Peroxisomes play a role in the regulation of tumorigenesis and cancer progression,...
BACKGROUND
Kidney clear cell carcinoma (KIRC) is the most common subtype of renal cell carcinoma. Peroxisomes play a role in the regulation of tumorigenesis and cancer progression, yet the prognostic significance of peroxisome-related genes (PRGs) remains rarely studied. The study aimed to establish a novel prognostic risk model and identify potential biomarkers in KIRC.
METHODS
The significant prognostic PRGs were screened through differential and Cox regression analyses, and LASSO Cox regression analysis was performed to establish a prognostic risk model in the training cohort, which was validated internally in the testing and entire cohorts, and further assessed in the GSE22541 cohort. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to explore the function and pathway differences between the high-risk and low-risk groups. The relationship between risk score and immune cell infiltration levels was evaluated in the CIBERSORT, ESTIMATE and TIMER databases. Finally, potential biomarkers were identified and validated from model genes, using immunohistochemistry.
RESULTS
Fourteen significant prognostic PRGs were identified using multiple analyses, and 9 genes (ABCD1, ACAD11, ACAT1, AGXT, DAO, EPHX2, FNDC5, HAO1, and HNGCLL1) were obtained to establish a prognostic model via LASSO Cox regression analysis. Combining the risk score with clinical factors to construct a nomogram, which provided support for personalized treatment protocols for KIRC patients. GO and KEGG analyses highlighted associations with substance metabolism, transport, and the PPAR signaling pathways. Tumor immune infiltration indicated immune suppression in the high-risk group, accompanied by higher tumor purity and the expression of 9 model genes was positively correlated with the level of immune cell infiltration. ACAT1 has superior prognostic capabilities in predicting the outcomes of KIRC patients.
CONCLUSIONS
The peroxisome-related prognostic risk model could better predict prognosis in KIRC patients.
Topics: Humans; Carcinoma, Renal Cell; Peroxisomes; Prognosis; Kidney Neoplasms; Biomarkers; Kidney; Fibronectins
PubMed: 38297313
DOI: 10.1186/s12894-024-01404-z -
BioRxiv : the Preprint Server For... Oct 2023Liquid-liquid phase separation (LLPS) underlies diverse biological processes. Because most LLPS studies were performed in vitro or in cells that overexpress protein, the...
Liquid-liquid phase separation (LLPS) underlies diverse biological processes. Because most LLPS studies were performed in vitro or in cells that overexpress protein, the physiological relevance of LLPS is unclear. PERIOD proteins are central mammalian circadian clock components and interact with other clock proteins in the core circadian negative feedback loop. Different core clock proteins were previously shown to form large complexes. Here we show that when transgene was stably expressed, PER2 formed nuclear phosphorylation-dependent LLPS condensates that recruited other clock proteins. Super-resolution microscopy of endogenous PER2, however, revealed formation of circadian-controlled, rapidly diffusing microbodies that were resistant to protein concentration changes, hexanediol treatment, and loss of phosphorylation, indicating that they are distinct from the LLPS condensates caused by overexpression. Surprisingly, only a small fraction of endogenous PER2 microbodies transiently interact with endogenous BMAL1 and CRY1, a conclusion that was confirmed in cells and in mice tissues, suggesting an enzyme-like mechanism in the circadian negative feedback process. Together, these results demonstrate that the dynamic interactions of core clock proteins is a key feature of mammalian circadian clock mechanism and the importance of examining endogenous proteins in LLPS and circadian studies.
PubMed: 37961341
DOI: 10.1101/2023.10.19.563153 -
PLoS Biology Apr 2024Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the...
Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.
Topics: Peroxisomes; Mitochondrial Dynamics; Mitochondria; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Fatty Acids; GTP Phosphohydrolases; Mitochondrial Proteins; Endoplasmic Reticulum; Membrane Proteins; Proteasome Endopeptidase Complex; Citric Acid Cycle; Membrane Potential, Mitochondrial; Mitochondrial Membranes; Humans
PubMed: 38669296
DOI: 10.1371/journal.pbio.3002602 -
International Journal of Molecular... Feb 2024Fatty acids and their derivatives play a variety of roles in living organisms. Fatty acids not only store energy but also comprise membrane lipids and act as signaling...
Fatty acids and their derivatives play a variety of roles in living organisms. Fatty acids not only store energy but also comprise membrane lipids and act as signaling molecules. There are three main proteins involved in the fatty acid β-oxidation pathway in plant peroxisomes, including acyl-CoA oxidase (), multifunctional protein (), and 3-ketolipoyl-CoA thiolase (). However, genome-scale analysis of and has not been systemically investigated in tomatoes. Here, we conducted a bioinformatics analysis of and genes in tomatoes. Their physicochemical properties, protein secondary structure, subcellular localization, gene structure, phylogeny, and collinearity were also analyzed. In addition, a conserved motif analysis, an evolutionary pressure selection analysis, a -acting element analysis, tissue expression profiling, and a qRT-PCR analysis were conducted within tomato KAT and MFP family members. There are five and four family members in tomatoes, which are randomly distributed on four chromosomes. By analyzing the conserved motifs of tomato and family members, we found that both and members are highly conserved. In addition, the results of the evolutionary pressure selection analysis indicate that the and family members have evolved mainly from purifying selection, which makes them more structurally stable. The results of the -acting element analysis show that and with respect may respond to light, hormones, and adversity stresses. The tissue expression analysis showed that and family members have important roles in regulating the development of floral organs as well as fruit ripening. The qRT-PCR analysis revealed that the expressions of and genes can be regulated by ABA, MeJA, darkness, NaCl, PEG, UV, cold, heat, and HO treatments. These results provide a basis for the involvement of the and genes in tomato floral organ development and abiotic stress response, which lay a foundation for future functional study of and in tomatoes.
Topics: Solanum lycopersicum; Oxidoreductases; Fatty Acids; Hydrogen Peroxide; Peroxisomes; Plant Proteins; Stress, Physiological; Phylogeny; Gene Expression Regulation, Plant; Multigene Family
PubMed: 38396949
DOI: 10.3390/ijms25042273