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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 -
Experimental Neurology Dec 2023Myocardial infarction (MI) induces inflammatory response and oxidative stress in the brain, which would be one of the causes of cardiac dysfunction. Exercise training is...
Resistance exercise alleviates the prefrontal lobe injury and dysfunction by activating SESN2/AMPK/PGC-1α signaling pathway and inhibiting oxidative stress and inflammation in mice with myocardial infarction.
OBJECTIVES
Myocardial infarction (MI) induces inflammatory response and oxidative stress in the brain, which would be one of the causes of cardiac dysfunction. Exercise training is viewed as a feasible strategy to improve cardiac function of the infarcted heart. The aim of this study was to investigate whether exercise training could alleviate MI-induced prefrontal lobe injury via activating Sestrin2 (SESN2) signaling and inhibiting oxidative stress and inflammation.
METHODS
Male C57BL/6 mice were divided into five groups: control group (CON), aerobic exercise group (AE), resistance exercise group (RE), whole-body vibration group (WBV) and electrical stimulation group (ES); and three groups: sham-operated group (S), sedentary MI group (MI) and MI with resistance exercise group (MRE). After four weeks of training, sensorimotor function, spatial learning, long-term and spatial memory, and cardiac function were detected. Then, mice were euthanized, and the prefrontal areas were separated for HE, Nissl, SESN2, microtubule-associated protein 2 (MAP2), neuron-specific nucleoprotein (NeuN), and TUNEL staining. Activation of SESN2/adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) signaling pathway and expression of proteins related to oxidative stress, inflammation and apoptosis in the prefrontal lobe were detected by western blotting.
RESULTS
Different types of exercise training all activated the SESN2/AMPK/PGC-1α signaling pathway, and the effect of RE is the best. RE improved sensorimotor, learning, and memory impairments, increased the expressions of antioxidant, anti-inflammatory and anti-apoptotic proteins, reduced oxidative stress, inflammation and apoptosis, ultimately alleviated the prefrontal lobe injury and dysfunction in mice with MI.
CONCLUSION
RE alleviates MI-indued prefrontal lobe injury and dysfunction by inhibiting the levels of oxidative stress, inflammation and apoptosis, partially via activating SESN2/AMPK/PGC-1α signaling pathway.
Topics: Humans; Mice; Animals; Male; AMP-Activated Protein Kinases; Resistance Training; Mice, Inbred C57BL; Myocardial Infarction; Signal Transduction; Oxidative Stress; Inflammation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sestrins
PubMed: 37788754
DOI: 10.1016/j.expneurol.2023.114559 -
BioRxiv : the Preprint Server For... Sep 2023Peroxisome biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital...
UNLABELLED
Peroxisome biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
SUMMARY
The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
PubMed: 37693581
DOI: 10.1101/2023.08.31.555756 -
Experimental Cell Research Jan 2024Liver fibrosis is a significant health burden worldwide and has emerged as the leading cause of Hepatocellular carcinoma (HCC) incidence. Mitochondria are the dynamic... (Review)
Review
Liver fibrosis is a significant health burden worldwide and has emerged as the leading cause of Hepatocellular carcinoma (HCC) incidence. Mitochondria are the dynamic organelles that regulate the differentiation, survival, and polarization of macrophages. Nuclear-DNA-associated proteins, micro-RNAs, as well as macrophage polarization are essential for maintaining intracellular and extra-cellular homeostasis in the liver parenchyma. Dysregulated mitochondrial coding genes (ETS complexes I, II, III, IV, and V), non-coding RNAs (mitomiRs), and nuclear alteration lead to the production of reactive oxygen species (ROS) and inflammation which are implicated in the transition of liver fibrosis into HCC. Recent findings indicated the protecting effect of E74-like factor 3/peroxisome proliferator-activated receptor-γ (Elf-3/PPAR-γ). HDAR-y inhibits the deacetylation of PPAR-y and maintains the PPAR-y pathway. Elf-3 plays a tumor suppressive role through epithelial-mesenchymal transition-related gene and zinc finger E-box binding homeobox 2 (ZEB-2) domain. Additionally, the development of HCC includes the PI3K/Akt/mTOR and transforming Growth Factor β (TGF-β) pathway that promotes the Epithelial-mesenchymal transition (EMT) through Smad/Snail/Slug signaling cascade. In contrast, the TLR2/NOX2/autophagy axis promotes M2 polarization in HCC. Thus, a thorough understanding of the mitochondrial and nuclear reciprocal relationship related to macrophage polarization could provide new research opportunities concerning diseases with a significant impact on liver parenchyma towards developing liver fibrosis or liver cancer. Moreover, this knowledge can be used to develop new therapeutic strategies to treat liver diseases.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Peroxisome Proliferator-Activated Receptors; Cell Line, Tumor; Signal Transduction; Liver Cirrhosis; Mitochondria; Macrophages; Epithelial-Mesenchymal Transition
PubMed: 38086504
DOI: 10.1016/j.yexcr.2023.113878 -
Free Radical Biology & Medicine Nov 2023In peroxisomes, acyl-CoA oxidase (ACOX) oxidizes fatty acids and produces HO, and the latter is decomposed by catalase. If ethanol is present, ethanol will be oxidized...
In peroxisomes, acyl-CoA oxidase (ACOX) oxidizes fatty acids and produces HO, and the latter is decomposed by catalase. If ethanol is present, ethanol will be oxidized by catalase coupling with decomposition of HO. Peroxisome proliferator-activated receptor α (PPARα) agonist WY-14,643 escalated ethanol clearance, which was not observed in catalase knockout (Cat) mice or partially blocked by an ACOX1 inhibitor. WY-14,643 induced peroxisome proliferation via peroxin 16 (PEX16). PEX16 liver-specific knockout (Pex16) mice lack intact peroxisomes in liver, but catalase and ACOX1 were upregulated. Due to lacking intact peroxisomes, the upregulated catalase and ACOX1 in the Pex16 mice were mislocated in cytosol and microsomes, and the escalated ethanol clearance was not observed in the Pex16 mice, implicating that the intact functional peroxisomes are essential for ACOX1/catalase to metabolize ethanol. Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from alcoholic steatosis to steatohepatitis. WY-14,643 ameliorated alcoholic steatosis but tended to enhance alcoholic steatohepatitis. In mice lacking nuclear factor erythroid 2-related factor 2 (Nrf2), WY-14,643 still induced PEX16, ACOX1 and catalase to escalate ethanol clearance and blunt alcoholic steatosis, which was not observed in the PPARα-absent Nrf2 mice (Pparα/Nrf2) mice, suggesting that WY-14,643 escalates ethanol clearance through PPARα but not through Nrf2.
Topics: Animals; Mice; Acyl-CoA Oxidase; Catalase; Cell Proliferation; Ethanol; Fatty Liver; Hydrogen Peroxide; Liver; Mice, Knockout; NF-E2-Related Factor 2; Peroxisomes; PPAR alpha
PubMed: 37567517
DOI: 10.1016/j.freeradbiomed.2023.08.016 -
Frontiers in Medicine 2024Endometriosis constitutes the most common cause of chronic pelvic pain in female patients and is associated with infertility. Although there is no known cause for the... (Review)
Review
Endometriosis constitutes the most common cause of chronic pelvic pain in female patients and is associated with infertility. Although there is no known cause for the disease, it is a heritable condition that is determined by numerous genetic, epigenetic, and environmental aspects. Peroxisome proliferator-activated receptors (PPARs) represent nuclear receptor proteins that control gene expression. By using the MEDLINE and LIVIVO databases we conducted a literature review in order to look into the role of PPARs in the endometriosis pathophysiology and succeeded in revealing 36 pertinent publications between 2001 and 2022. In regards to PPAR expression in endometriosis, PPARγ seems to represent the most studied PPAR isoform in endometriosis and to influence various pathways involved in the disease onset and progression. It's interesting to note that diverse treatment agents targeting the PPAR system have been identified as innovative, effective therapeutic alternatives in the context of endometriosis treatment. In conclusion, PPARs appear to contribute an important role in both endometriosis pathophysiology and therapy.
PubMed: 38690174
DOI: 10.3389/fmed.2024.1329406 -
Basic & Clinical Pharmacology &... Mar 2024Bile acids are synthesized from cholesterol in the liver. Dysregulation of bile acid homeostasis, characterized by excessive accumulation in the liver, gallbladder and... (Review)
Review
Bile acids are synthesized from cholesterol in the liver. Dysregulation of bile acid homeostasis, characterized by excessive accumulation in the liver, gallbladder and blood, can lead to hepatocellular damage and the development of cholestatic liver disease. Nuclear receptors play a crucial role in the control of bile acid metabolism by efficiently regulating bile acid synthesis and transport in the liver. Among these receptors, peroxisome proliferator-activated receptor (PPAR), a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily, controls the expression of genes involved in adipogenesis, lipid metabolism, inflammation and glucose homeostasis and has emerged as a potential therapeutic target for the treatment of the metabolic syndrome in the past two decades. Emerging evidence suggests that PPAR activation holds promise as a therapeutic target for cholestatic liver disease, as it affects both bile acid production and transport. This review provides a comprehensive overview of recent advances in elucidating the role of PPAR in the regulation of bile acid metabolism, highlighting the current position of PPAR agonists in the treatment of primary biliary cholangitis. By summarizing the specific regulatory effects of PPAR on bile acids, this review contributes to the exploration of novel therapeutic strategies for cholestatic liver diseases.
Topics: Humans; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Bile Acids and Salts; Lipid Metabolism; Liver Diseases
PubMed: 38048777
DOI: 10.1111/bcpt.13971 -
Revista Da Associacao Medica Brasileira... 2024Obesity is an increasingly prevalent global health problem, which is generally caused by the increase in body fat mass above normal and observed in all societies. If the...
OBJECTIVE
Obesity is an increasingly prevalent global health problem, which is generally caused by the increase in body fat mass above normal and observed in all societies. If the blood glucose level is higher than normal but not high enough to diagnose diabetes, this condition is defined as prediabetes. Adiponectin increases fatty acid oxidation and insulin sensitivity and is closely associated with obesity. One of the nuclear receptor superfamily member peroxisome proliferator-activated receptors is shown to have an important role in various metabolic reactions. This study aimed to investigate the serum levels of adiponectin and peroxisome proliferator-activated receptors-gamma parameters, which are closely related to adipose tissue, energy metabolism, and insulin sensitivity, in obese patients with and without prediabetes.
METHODS
For this purpose, 52 obese patients with prediabetes, 48 obese patients with non-prediabetes, and 76 healthy individuals were included in this study. Serum adiponectin and peroxisome proliferator-activated receptors-γ levels were analyzed by ELISA.
RESULTS
Serum adiponectin levels were significantly higher in obese patients with prediabetes (18.15±15.99) compared with the control group (15.17±15.67; p=0.42). No significant difference was observed in both adiponectin and peroxisome proliferator-activated receptors-γ levels in the obese patients with the non-prediabetes group compared with the control group. However, no significant difference was observed in the obese patients with prediabetes group and obese patients with non-prediabetes group.
CONCLUSION
Our results suggest that adiponectin may serve as an indicator of prediabetes. This implies that examining adiponectin levels in individuals diagnosed with prediabetes may enhance our understanding of the metabolic processes closely linked to prediabetes and related conditions.
Topics: Humans; Prediabetic State; PPAR gamma; Obesity; Adiponectin; Female; Male; Adult; Middle Aged; Case-Control Studies; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Blood Glucose; Insulin Resistance
PubMed: 38655997
DOI: 10.1590/1806-9282.20231000 -
Frontiers in Microbiology 2023Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver disease induced by chronic hepatitis C virus (HCV)...
Despite the introduction of effective treatments for hepatitis C in clinics, issues remain regarding the liver disease induced by chronic hepatitis C virus (HCV) infection. HCV is known to disturb the metabolism of infected cells, especially lipid metabolism and redox balance, but the mechanisms leading to HCV-induced pathogenesis are still poorly understood. In an APEX2-based proximity biotinylation screen, we identified ACBD5, a peroxisome membrane protein, as located in the vicinity of HCV replication complexes. Confocal microscopy confirmed the relocation of peroxisomes near HCV replication complexes and indicated that their morphology and number are altered in approximately 30% of infected Huh-7 cells. Peroxisomes are small versatile organelles involved among other functions in lipid metabolism and ROS regulation. To determine their importance in the HCV life cycle, we generated Huh-7 cells devoid of peroxisomes by inactivating the PEX5 and PEX3 genes using CRISPR/Cas9 and found that the absence of peroxisomes had no impact on replication kinetics or infectious titers of HCV strains JFH1 and DBN3a. The impact of HCV on peroxisomal functions was assessed using sub-genomic replicons. An increase of ROS was measured in peroxisomes of replicon-containing cells, correlated with a significant decrease of catalase activity with the DBN3a strain. In contrast, HCV replication had little to no impact on cytoplasmic and mitochondrial ROS, suggesting that the redox balance of peroxisomes is specifically impaired in cells replicating HCV. Our study provides evidence that peroxisome function and morphology are altered in HCV-infected cells.
PubMed: 37808318
DOI: 10.3389/fmicb.2023.1254728 -
Frontiers in Physiology 2023
PubMed: 38143916
DOI: 10.3389/fphys.2023.1338852