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Biochemical Society Transactions Dec 2023Plant organelles predominantly rely on the actin cytoskeleton and the myosin motors for long-distance trafficking, while using microtubules and the kinesin motors mostly...
Plant organelles predominantly rely on the actin cytoskeleton and the myosin motors for long-distance trafficking, while using microtubules and the kinesin motors mostly for short-range movement. The distribution and motility of organelles in the plant cell are fundamentally important to robust plant growth and defense. Chloroplasts, mitochondria, and peroxisomes are essential organelles in plants that function independently and coordinately during energy metabolism and other key metabolic processes. In response to developmental and environmental stimuli, these energy organelles modulate their metabolism, morphology, abundance, distribution and motility in the cell to meet the need of the plant. Consistent with their metabolic links in processes like photorespiration and fatty acid mobilization is the frequently observed inter-organellar physical interaction, sometimes through organelle membranous protrusions. The development of various organelle-specific fluorescent protein tags has allowed the simultaneous visualization of organelle movement in living plant cells by confocal microscopy. These energy organelles display an array of morphology and movement patterns and redistribute within the cell in response to changes such as varying light conditions, temperature fluctuations, ROS-inducible treatments, and during pollen tube development and immune response, independently or in association with one another. Although there are more reports on the mechanism of chloroplast movement than that of peroxisomes and mitochondria, our knowledge of how and why these three energy organelles move and distribute in the plant cell is still scarce at the functional and mechanistic level. It is critical to identify factors that control organelle motility coupled with plant growth, development, and stress response.
Topics: Organelles; Actin Cytoskeleton; Peroxisomes; Chloroplasts; Mitochondria; Microtubules
PubMed: 37975429
DOI: 10.1042/BST20221093 -
Clinical Nutrition (Edinburgh, Scotland) Feb 2024Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the... (Review)
Review
Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the key hallmarks of cancer is the reprogramming of metabolic pathways, especially abnormal lipid metabolism. Alterations in lipid uptake, lipid desaturation, de novo lipogenesis, lipid droplets, and fatty acid oxidation in cancer cells all contribute to cell survival in a changing microenvironment by regulating feedforward oncogenic signals, key oncogenic functions, oxidative and other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by fatty acids and act as core lipid sensors involved in the regulation of lipid homeostasis and cell fate. In addition to regulating whole-body energy homeostasis in physiological states, PPARs play a key role in lipid metabolism in cancer, which is receiving increasing research attention, especially the fundamental molecular mechanisms and cancer therapies targeting PPARs. In this review, we discuss how cancer cells alter metabolic patterns and regulate lipid metabolism to promote their own survival and progression through PPARs. Finally, we discuss potential therapeutic strategies for targeting PPARs in cancer based on recent studies from the last five years.
Topics: Humans; Peroxisome Proliferator-Activated Receptors; Lipid Metabolism; Transcription Factors; Fatty Acids; Cell Differentiation; Neoplasms
PubMed: 38142478
DOI: 10.1016/j.clnu.2023.12.005 -
International Journal of Biological... 2024Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Diabetes Mellitus, Type 2; Receptors, Cytoplasmic and Nuclear; Liver
PubMed: 38164174
DOI: 10.7150/ijbs.87305 -
Journal of Cellular and Molecular... Jan 2024Insulin resistance is a significant contributor to the development of type 2 diabetes (T2D) and is associated with obesity, physical inactivity, and low maximal oxygen... (Review)
Review
Insulin resistance is a significant contributor to the development of type 2 diabetes (T2D) and is associated with obesity, physical inactivity, and low maximal oxygen uptake. While intense and prolonged exercise may have negative effects, physical activity can have a positive influence on cellular metabolism and the immune system. Moderate exercise has been shown to reduce oxidative stress and improve antioxidant status, whereas intense exercise can increase oxidative stress in the short term. The impact of exercise on pro-inflammatory cytokine production is complex and varies depending on intensity and duration. Exercise can also counteract the harmful effects of ageing and inflamm-ageing. This review aims to examine the molecular pathways altered by exercise in non-obese individuals at higher risk of developing T2D, including glucose utilization, lipid metabolism, mitochondrial function, inflammation and oxidative stress, with the potential to improve insulin sensitivity. The focus is on understanding the potential benefits of exercise for improving insulin sensitivity and providing insights for future targeted interventions before onset of disease.
Topics: Humans; Insulin Resistance; Diabetes Mellitus, Type 2; Obesity; Antioxidants; Oxidative Stress; Exercise; Insulin
PubMed: 37938877
DOI: 10.1111/jcmm.18015 -
Free Radical Biology & Medicine Sep 2023Reduced (NADH) and oxidized (NAD) nicotinamide adenine dinucleotides are ubiquitous hydride-donating/accepting cofactors that are essential for cellular bioenergetics....
Reduced (NADH) and oxidized (NAD) nicotinamide adenine dinucleotides are ubiquitous hydride-donating/accepting cofactors that are essential for cellular bioenergetics. Peroxisomes are single-membrane-bounded organelles that are involved in multiple lipid metabolism pathways, including beta-oxidation of fatty acids, and which contain several NAD(H)-dependent enzymes. Although maintenance of NAD(H) homeostasis in peroxisomes is considered essential for peroxisomal beta-oxidation, little is known about the regulation thereof. To resolve this issue, we have developed methods to specifically measure intraperoxisomal NADH levels in human cells using peroxisome-targeted NADH biosensors. By targeted CRISPR-Cas9-mediated genome editing of human cells, we showed with these sensors that the NAD/NADH ratio in cytosol and peroxisomes are closely connected and that this crosstalk is mediated by intraperoxisomal lactate and malate dehydrogenases, generated via translational stop codon readthrough of the LDHB and MDH1 mRNAs. Our study provides evidence for the existence of two independent redox shuttle systems in human peroxisomes that regulate peroxisomal NAD/NADH homeostasis. This is the first study that shows a specific metabolic function of protein isoforms generated by translational stop codon readthrough in humans.
Topics: Humans; NAD; Codon, Terminator; Peroxisomes; Protein Biosynthesis; Oxidation-Reduction; Homeostasis
PubMed: 37355054
DOI: 10.1016/j.freeradbiomed.2023.06.020 -
Journal of Lipid Research Sep 2023N-acyl taurines (NATs) are bioactive lipids with emerging roles in glucose homeostasis and lipid metabolism. The acyl chains of hepatic and biliary NATs are enriched in...
N-acyl taurines (NATs) are bioactive lipids with emerging roles in glucose homeostasis and lipid metabolism. The acyl chains of hepatic and biliary NATs are enriched in polyunsaturated fatty acids (PUFAs). Dietary supplementation with a class of PUFAs, the omega-3 fatty acids, increases their cognate NATs in mice and humans. However, the synthesis pathway of the PUFA-containing NATs remains undiscovered. Here, we report that human livers synthesize NATs and that the acyl-chain preference is similar in murine liver homogenates. In the mouse, we found that hepatic NAT synthase activity localizes to the peroxisome and depends upon an active-site cysteine. Using unbiased metabolomics and proteomics, we identified bile acid-CoA:amino acid N-acyltransferase (BAAT) as the likely hepatic NAT synthase in vitro. Subsequently, we confirmed that BAAT knockout livers lack up to 90% of NAT synthase activity and that biliary PUFA-containing NATs are significantly reduced compared with wildtype. In conclusion, we identified the in vivo PUFA-NAT synthase in the murine liver and expanded the known substrates of the bile acid-conjugating enzyme, BAAT, beyond classic bile acids to the synthesis of a novel class of bioactive lipids.
Topics: Mice; Humans; Animals; Bile Acids and Salts; Taurine; Liver; Fatty Acids, Unsaturated; Acyltransferases; Amino Acids; Fatty Acids; Fatty Acids, Omega-3
PubMed: 36958721
DOI: 10.1016/j.jlr.2023.100361 -
Nature Communications Sep 2023The double-ring AAA+ ATPase Pex1/Pex6 is required for peroxisomal receptor recycling and is essential for peroxisome formation. Pex1/Pex6 mutations cause severe...
The double-ring AAA+ ATPase Pex1/Pex6 is required for peroxisomal receptor recycling and is essential for peroxisome formation. Pex1/Pex6 mutations cause severe peroxisome associated developmental disorders. Despite its pathophysiological importance, mechanistic details of the heterohexamer are not yet available. Here, we report cryoEM structures of Pex1/Pex6 from Saccharomyces cerevisiae, with an endogenous protein substrate trapped in the central pore of the catalytically active second ring (D2). Pairs of Pex1/Pex6(D2) subdomains engage the substrate via a staircase of pore-1 loops with distinct properties. The first ring (D1) is catalytically inactive but undergoes significant conformational changes resulting in alternate widening and narrowing of its pore. These events are fueled by ATP hydrolysis in the D2 ring and disengagement of a "twin-seam" Pex1/Pex6(D2) heterodimer from the staircase. Mechanical forces are propagated in a unique manner along Pex1/Pex6 interfaces that are not available in homo-oligomeric AAA-ATPases. Our structural analysis reveals the mechanisms of how Pex1 and Pex6 coordinate to achieve substrate translocation.
Topics: ATPases Associated with Diverse Cellular Activities; Cryoelectron Microscopy; Mutation; Peroxisomes; Proton-Translocating ATPases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Substrate Specificity
PubMed: 37741838
DOI: 10.1038/s41467-023-41640-9 -
Trends in Cell Biology Sep 2023Since their discovery, members of the gasdermin (GSDM) family of proteins have been firmly established as executors of pyroptosis, with the N-terminal fragment of most... (Review)
Review
Since their discovery, members of the gasdermin (GSDM) family of proteins have been firmly established as executors of pyroptosis, with the N-terminal fragment of most GSDMs capable of forming pores in the plasma membrane. More recent findings suggest that some GSDMs can drive additional cell death pathways, such as apoptosis and necroptosis, through mechanisms independent of plasma membrane perforation. There is also emerging evidence that by associating with cellular compartments such as mitochondria, peroxisomes, endosomes, and the nucleus, GSDMs regulate cell death-independent aspects of cellular homeostasis. Here, we review the diversity of GSDM function across several cell types and explore how various cellular stresses can promote relocalization - and thus refunctionalization - of GSDMs.
Topics: Humans; Gasdermins; Neoplasm Proteins; Apoptosis; Pyroptosis; Homeostasis; Inflammasomes
PubMed: 37062616
DOI: 10.1016/j.tcb.2023.02.007 -
Hypertension (Dallas, Tex. : 1979) Nov 2023Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress,...
BACKGROUND
Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress, hypertension, and maternal systemic organ damage. The transcription factor, PPARγ (peroxisome proliferator-activated receptor-γ) promotes healthy trophoblast differentiation but is dysregulated in the preeclampsia placenta. Our study identifies the beneficial impact of Rosiglitazone-mediated PPARγ-activation in the stressed preeclampsia placenta.
METHODS
We used first trimester placentas, preeclamptic and preterm control placentas, and human trophoblast cell lines to study PPARγ activation.
RESULTS
Induction of PPARγ activates cell growth and antioxidative stress pathways, including the gene, heme oxygenase 1 (). Protein expression of both PPARγ and HO1 (heme oxygenase 1) are reduced in preeclamptic placentas, but Rosiglitazone restores HO1 signaling in a PPARγ-dependent manner.
CONCLUSIONS
Restoring disrupted pathways by PPARγ in preeclampsia offers a potential therapeutic pathway to reverse placental damage, extending pregnancy duration, and reduce maternal sequelae. Future research should aim to understand the full scope of impaired PPARγ signaling in the human placenta and focus on compounds for safe use during pregnancy to prevent severe perinatal morbidity and mortality.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Heme Oxygenase-1; Placenta; PPAR gamma; Pre-Eclampsia; Rosiglitazone; Trophoblasts
PubMed: 37702083
DOI: 10.1161/HYPERTENSIONAHA.123.21645 -
EMBO Reports Dec 2023Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with roles in mitochondrial quality...
Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin-sensitive, and protected from diet-induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL-dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell-autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis.
Topics: Animals; Mice; Bile; Bile Acids and Salts; Liver; Mice, Knockout; Mitochondrial Proteins; Ubiquitin-Protein Ligases; Ubiquitins
PubMed: 37962001
DOI: 10.15252/embr.202357972