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The Journal of Cell Biology Oct 2023Mitochondria are dynamic organelles regulated by fission and fusion processes. The fusion of membranes requires elaborative coordination of proteins and lipids and is...
Mitochondria are dynamic organelles regulated by fission and fusion processes. The fusion of membranes requires elaborative coordination of proteins and lipids and is particularly crucial for the function and quality control of mitochondria. Phosphatidic acid (PA) on the mitochondrial outer membrane generated by PLD6 facilitates the fusion of mitochondria. However, how PA promotes mitochondrial fusion remains unclear. Here, we show that a mitochondrial outer membrane protein, NME3, is required for PLD6-induced mitochondrial tethering or clustering. NME3 is enriched at the contact interface of two closely positioned mitochondria depending on PLD6, and NME3 binds directly to PA-exposed lipid packing defects via its N-terminal amphipathic helix. The PA binding function and hexamerization confer NME3 mitochondrial tethering activity. Importantly, nutrient starvation enhances the enrichment efficiency of NME3 at the mitochondrial contact interface, and the tethering ability of NME3 contributes to fusion efficiency. Together, our findings demonstrate NME3 as a tethering protein promoting selective fusion between PLD6-remodeled mitochondria for quality control.
Topics: Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; NM23 Nucleoside Diphosphate Kinases; Phosphatidic Acids; Phospholipase D
PubMed: 37584589
DOI: 10.1083/jcb.202301091 -
Biochemical Pharmacology Feb 2024Phosphatidylinositol 4-kinases (PI4Ks) could phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P) and maintain its metabolic... (Review)
Review
Phosphatidylinositol 4-kinases (PI4Ks) could phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P) and maintain its metabolic balance and location. PI4P, the most abundant monophosphate inositol in eukaryotic cells, is a precursor of higher phosphoinositols and an essential substrate for the PLC/PKC and PI3K/Akt signaling pathways. PI4Ks regulate vesicle transport, signal transduction, cytokinesis, and cell unity, and are involved in various physiological and pathological processes, including infection and growth of parasites such as Plasmodium and Cryptosporidium, replication and survival of RNA viruses, and the development of tumors and nervous system diseases. The development of novel drugs targeting PI4Ks and PI4P has been the focus of the research and clinical application of drugs, especially in recent years. In particular, PI4K inhibitors have made great progress in the treatment of malaria and cryptosporidiosis. We describe the biological characteristics of PI4Ks; summarize the physiological functions and effector proteins of PI4P; and analyze the structural basis of selective PI4K inhibitors for the treatment of human diseases in this review. Herein, this review mainly summarizes the developments in the structure and enzyme activity of PI4K inhibitors.
Topics: Humans; 1-Phosphatidylinositol 4-Kinase; Phosphatidylinositol 3-Kinases; Cryptosporidiosis; Cryptosporidium; Phosphatidylinositol Phosphates; Phosphatidylinositols
PubMed: 38151075
DOI: 10.1016/j.bcp.2023.115993 -
Diabetes Care Sep 2023Few trials studied the links of food components in different diets with their induced lipidomic changes and related metabolic outcomes. Thus, we investigated specific... (Randomized Controlled Trial)
Randomized Controlled Trial
Diet-Related Lipidomic Signatures and Changed Type 2 Diabetes Risk in a Randomized Controlled Feeding Study With Mediterranean Diet and Traditional Chinese or Transitional Diets.
OBJECTIVE
Few trials studied the links of food components in different diets with their induced lipidomic changes and related metabolic outcomes. Thus, we investigated specific lipidomic signatures with habitual diets and modified diabetes risk by using a trial and a cohort.
RESEARCH DESIGN AND METHODS
We included 231 Chinese with overweight and prediabetes in a randomized feeding trial with Mediterranean, traditional, or transitional diets (control diet) from February to September 2019. Plasma lipidomic profiles were measured at baseline, third month, and sixth month by high-throughput targeted liquid chromatography-mass spectrometry. Associations of the identified lipids with habitual dietary intakes were examined in another lipidomic database of a Chinese cohort (n = 1,117). The relationships between diet-induced changes of lipidomic species and diabetes risk factors were further investigated through both individual lipids and relevant modules in the trial.
RESULTS
Out of 364 lipidomic species, 26 altered across groups, including 12 triglyceride (TAG) fractions, nine plasmalogens, four phosphatidylcholines (PCs), and one phosphatidylethanolamine. TAG fractions and PCs were associated with habitual fish intake while plasmalogens were associated with red meat intake in the cohort. Of the diet-related lipidomic metabolites, 10 TAG fractions and PC(16:0/22:6) were associated with improved Matsuda index (β = 0.12 to 0.42; PFDR < 0.030). Two plasmalogens were associated with deteriorated fasting glucose (β = 0.29 to 0.31; PFDR < 0.014). Similar results were observed for TAG and plasmalogen related modules.
CONCLUSIONS
These fish- and red meat-related lipidomic signatures sensitively reflected different diets and modified type 2 diabetes risk factors, critical for optimizing dietary patterns.
Topics: Animals; Humans; Diet, Mediterranean; Diabetes Mellitus, Type 2; Lipidomics; East Asian People; Plasmalogens; Diet
PubMed: 37463495
DOI: 10.2337/dc23-0314 -
Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity.BioRxiv : the Preprint Server For... Mar 2024Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively...
Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibited PIEZO2, but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analogue carbocyclic phosphatidic acid (ccPA) also inhibited PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibited PIEZO2, but not PIEZO1. Conversely, inhibiting PLD led to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.
PubMed: 38464030
DOI: 10.1101/2024.03.01.582964 -
International Journal of Molecular... Aug 2023Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell... (Review)
Review
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.
Topics: Humans; Receptors, Lysophosphatidic Acid; Lysophospholipids; Macrophages; Inflammation
PubMed: 37569902
DOI: 10.3390/ijms241512524 -
PloS One 2023Extracellular vesicles (EVs) (exossomes, microvesicles and apoptotic bodies) have been well acknowledged as mediators of intercellular communications in prokaryotes and...
Extracellular vesicles (EVs) (exossomes, microvesicles and apoptotic bodies) have been well acknowledged as mediators of intercellular communications in prokaryotes and eukaryotes. Lipids are essential molecular components of EVs but at the moment the knowledge about the lipid composition and the function of lipids in EVs is limited and as for now none lipidomic studies in Giardia EVs was described. Therefore, the focus of the current study was to conduct, for the first time, the characterization of the polar lipidome, namely phospholipid and sphingolipid profiles of G. lamblia trophozoites, microvesicles (MVs) and exosomes, using C18-Liquid Chromatography-Mass Spectrometry (C18-LC-MS) and Tandem Mass Spectrometry (MS/MS). A total of 162 lipid species were identified and semi-quantified, in the trophozoites, or in the MVs and exosomes belonging to 8 lipid classes, including the phospholipid classes phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), cardiolipins (CL), the sphingolipid classes sphingomyelin (SM) and ceramides (Cer), and cholesterol (ST), and 3 lipid subclasses that include lyso PC (LPC), lyso PE (LPE) and lyso PG (LPG), but showing different abundances. This work also identified, for the first time, in G. lamblia trophozoites, the lipid classes CL, Cer and ST and subclasses of LPC, LPE and LPG. Univariate and multivariate analysis showed clear discrimination of lipid profiles between trophozoite, exosomes and MVs. The principal component analysis (PCA) plot of the lipidomics dataset showed clear discrimination between the three groups. Future studies focused on the composition and functional properties of Giardia EVs may prove crucial to understand the role of lipids in host-parasite communication, and to identify new targets that could be exploited to develop novel classes of drugs to treat giardiasis.
Topics: Animals; Giardia lamblia; Lipidomics; Tandem Mass Spectrometry; Extracellular Vesicles; Giardiasis; Giardia; Ceramides; Lecithins; Phospholipids; Sphingolipids; Cardiolipins; Gastropoda
PubMed: 37683041
DOI: 10.1371/journal.pone.0291292 -
Biomedicines Oct 2023Osteoarthritis (OA), a chronic degenerative joint disease, is the most common form of arthritis. OA occurs when the protective cartilage that cushions the ends of bones... (Review)
Review
Osteoarthritis (OA), a chronic degenerative joint disease, is the most common form of arthritis. OA occurs when the protective cartilage that cushions the ends of bones gradually breaks down. This leads to the rubbing of bones against each other, resulting in pain and stiffness. Cyclic phosphatidic acid (cPA) shows promise as a treatment for OA. In this article, we review the most recent findings regarding the biological functions of cPA signaling in mammalian systems, specifically in relation to OA. cPA is a naturally occurring phospholipid mediator with unique cyclic phosphate rings at the sn-2 and sn-3 positions in the glycerol backbone. cPA promotes various responses, including cell proliferation, migration, and survival. cPA possesses physiological activities that are distinct from those elicited by lysophosphatidic acid; however, its biochemical origin has rarely been studied. Although there is currently no cure for OA, advances in medical research may lead to new therapies or strategies in the future, and cPA has potential therapeutic applications.
PubMed: 37893163
DOI: 10.3390/biomedicines11102790 -
Cell Reports Sep 2023Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially...
Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.
Topics: Cell Line; Fatty Acids, Unsaturated; Ferroptosis; Phosphatidylinositols; Phospholipids; Humans
PubMed: 37691145
DOI: 10.1016/j.celrep.2023.113023 -
Scientific Reports Nov 2023Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic lipid accumulation due to impaired lipid metabolism. Although a correlation was found...
Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic lipid accumulation due to impaired lipid metabolism. Although a correlation was found between NAFLD and sphingosine-1-phosphate (S1P), the role of the sphingolipid remains controversial. The aim of this study was to investigate any involvement of S1P in steatosis using its analog FTY720P and HepG2 cells. Lipid accumulation was induced by incubating the cells in a mixture of oleic and palmitic acid, and was quantified using Oil Red O. The involvement of signaling mediators was studied using pharmacological inhibitors and western blot analysis. FTY720P increased lipid accumulation, but this increase wasn't maintained in the presence of inhibitors of S1PR3, Gq, SREBP, mTOR, PI3K, and PPARγ indicating their involvement in the process. The results revealed that FTY720P binds to S1PR3 which activates sequentially Gq, PI3K, and mTOR leading to an increase in SREBP expression and PPARγ activation. It was concluded that in presence of a high level of fatty acids, lipid accumulation is increased in hepatocytes by the exogenously added FTY720P.
Topics: Humans; Hep G2 Cells; Non-alcoholic Fatty Liver Disease; Sterol Regulatory Element Binding Protein 1; PPAR gamma; Liver; TOR Serine-Threonine Kinases; Lipid Metabolism; Lysophospholipids; Phosphatidylinositol 3-Kinases
PubMed: 37953311
DOI: 10.1038/s41598-023-46011-4 -
Gastroenterology Oct 2023Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have...
BACKGROUND & AIMS
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
METHODS
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
RESULTS
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
CONCLUSIONS
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Topics: Humans; Acute Disease; Pancreatitis; Fatty Acids, Nonesterified; Oleic Acid; Inflammation; Albumins; Phosphatidylcholines
PubMed: 37263302
DOI: 10.1053/j.gastro.2023.05.034