Journal of Lipid Research最新文献

{"title":"Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function?","authors":"Graeme I Lancaster, Andrew J Murphy","doi":"10.1016/j.jlr.2025.100765","DOIUrl":"10.1016/j.jlr.2025.100765","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of cell death driven by the excessive peroxidation of poly-unsaturated fatty acids (PUFAs) within membrane phospholipids. Ferroptosis is a hallmark of many diseases and preventing or inducing ferroptosis has considerable therapeutic potential. Like other forms of cell death, the pathological importance and therapeutic potential of ferroptosis is well appreciated. However, while cell death modalities such as apoptosis and necroptosis have critical physiological roles, such as in development and tissue homeostasis, whether ferroptosis has important physiological roles is largely unknown. In this regard, key questions for field are as follows: Is ferroptosis used for physiological processes? Are certain cell-types purposely adapted to be either resistant or sensitive to ferroptosis to be able to function optimally? Do physiological perturbations such as aging and diet impact ferroptosis susceptibility? Herein, we have reviewed emerging evidence that supports the idea that being able to selectively and controllably induce or resist ferroptosis is essential for development and cell function. While several factors regulate ferroptosis, it appears that the ability of cells and tissues to control their lipid composition, specifically the abundance of phospholipids containing PUFAs, is crucial for cells to be able to either resist or be sensitized to ferroptosis. Finally, aging and diets enriched in specific PUFAs lead to an increase in cellular PUFA levels which may sensitize cells to ferroptosis. Therefore, changes in dietary PUFAs or againg may impact the pathogenesis of diseases where ferroptosis is involved.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100765"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of genetic markers related to hyper-HDL cholesterol on the prevalence of myocardial infarction: a KoGES study.","authors":"Sung-Bum Lee, Kyung-Won Hong, Byoungjin Park, Dong-Hyuk Jung","doi":"10.1016/j.jlr.2025.100777","DOIUrl":"10.1016/j.jlr.2025.100777","url":null,"abstract":"<p><p>Recent studies have shown that hyper-high-density lipoprotein cholesterol (HDL-C) is associated with cardiovascular disease risk and all-cause mortality, a phenomenon known as the HDL-C paradox. Several genes have been reported to show relationships between increased HDL-C and myocardial infarction (MI) risk. We investigated the genetic predisposition of lipid metabolism influencing MI. The study dataset was from the Korean Genome and Epidemiology cohort obtained from the National Biobank of Korea, with an initial population of 68,806 individuals. We categorized samples based on HDL-C levels into hypo-HDL-C (n = 25,884), normal-HDL-C (n = 41,117), and hyper-HDL-C groups (n = 1,805). We conducted genome-wide association studies for each group and the total sample. Significant associations were defined using genome-wide significant level and suggestive level. The lead SNP of each locus was selected for further interpretation. This analysis included 2,014 (2.6%) MI patients. Using multivariable logistic regression, we evaluated the association of 7,877 SNPs in nine loci. We identified six SNPs significantly related to both hypo- and hyper-HDL groups, one SNP associated with hyper-HDL, and six SNPs associated with hypo-HDL group. Additionally, we found three SNPs associated with MI prevalence in the hyper-HDL group, including one significant SNP and two suggestive SNPs. Contrary to the traditional view of HDL-C as protective, this study identified genetic variants that increase MI risk by more than six-fold. These SNPs could play a role as important markers for detecting MI in hyper-HDL cholesterol group.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100777"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Foamy monocytes and atherogenesis in mice with combined hyperlipidemia and effects of antisense knockdown of apoCIII.","authors":"Xueying Peng, Zeqin Lian, Veronica O'Brien, Jing Xiao, Benjamin A Litchfield, Xiao-Yuan Dai Perrard, Lu Xu, Jing Ni, Aparna Mukherjee, Timothy Simmons, Henry Dong, Adam E Mullick, Rosanne Crooke, Henry J Pownall, Scott I Simon, Christie M Ballantyne, Huaizhu Wu","doi":"10.1016/j.jlr.2025.100763","DOIUrl":"10.1016/j.jlr.2025.100763","url":null,"abstract":"<p><p>Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr^-/- mice (Ldlr^-/-ApoCIIItg) fed Western high-fat diet (WD). Tissue culture with THP-1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins on monocytes. Ldlr^-/-ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr^-/- mice, Ldlr^-/-ApoCIIItg mice fed WD had early and persistent increases in lipid accumulation within monocytes and enhanced atherosclerosis. Ldlr^-/-ApoCIIItg mice versus Ldlr^-/- mice had higher levels of CD11c, CD36, and cytokines in foamy monocytes, with increases in foamy monocyte adhesion to vascular cell adhesion molecule-1 and oxidized LDL uptake. Monocytes took up TG-rich lipoprotein in vivo and in vitro and changed phenotypes. Foamy monocytes infiltrated into atherosclerotic lesions, and specific and sustained depletion of CD11c⁺ (foamy) monocytes profoundly reduced atherosclerosis in Ldlr^-/-ApoCIIItg mice on WD. Treatment with apoCIII ASO lowered plasma TG and cholesterol levels, improved foamy monocyte phenotypes, and reduced atherosclerosis in Ldlr^-/-ApoCIIItg mice. In conclusion, HTG in combined hyperlipidemia accelerates atherosclerosis, in part, by increasing foamy monocyte formation and infiltration into atherosclerotic plaques. Treatment with apoCIII ASO is a potential new therapy for improving monocyte phenotypes and reducing atherosclerosis in combined hyperlipidemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100763"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin regulates lymphatic endothelial integrity via palmitoylation.","authors":"Silvia Gonzalez-Nieves, Xiaochao Wei, Simon Guignard, Thi Nguyen, Jay McQuillan, Qiang Zhang, Jinsong Zhang, Reagan M McGuffee, David A Ford, Clay F Semenkovich, Vincenza Cifarelli","doi":"10.1016/j.jlr.2025.100775","DOIUrl":"10.1016/j.jlr.2025.100775","url":null,"abstract":"<p><p>Lipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and vessel maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. Thus, understanding how lipid metabolism affects LECs is critical for uncovering the mechanisms underlying lymphatic dysfunction. Protein palmitoylation, a lipid-based post-translational modification, has emerged as a critical regulator of protein function, stability, and interaction networks. Insulin, a master regulator of systemic lipid metabolism, also regulates protein palmitoylation. However, the role of insulin-driven palmitoylation in LEC biology remains unexplored. To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin-regulated targets, and determined the role of palmitoylation in LEC barrier function. In unstimulated conditions, palmitoylation occurred primarily on proteins involved in vesicular and membrane trafficking, and in translation initiation. Insulin treatment, instead, enriched palmitoylation of proteins involved in LEC integrity, namely junctional proteins such as claudin 5, along with small GTPases and ubiquitination enzymes. We also investigated the role of the long-chain fatty acid transporter CD36, a major mediator of palmitate uptake into cells, in regulating optimal lymphatic protein palmitoylation. CD36 silencing in LECs increased by 2-fold palmitoylation of proteins involved in inflammation and immune cell activation. Overall, our findings provide novel insights into the intricate relationship between lipid modification and LEC function, suggesting that insulin and palmitoylation play a critical role in lymphatic endothelial function.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100775"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of TMEM86A and TMEM86B mutants by a novel lysoplasmalogenase assay.","authors":"Denise Kummer, Ilaria Dorigatti, Theresia Dunzendorfer-Matt, Georg Golderer, Ernst R Werner, Katrin Watschinger","doi":"10.1016/j.jlr.2025.100766","DOIUrl":"10.1016/j.jlr.2025.100766","url":null,"abstract":"<p><p>Plasmalogens are an abundant class of glycero-phospholipids with a characteristic 1-O-alk-1'-enyl double bond. While their synthesis has been extensively investigated, their degradation remains understudied. Plasmalogen deficiencies are associated with severe disorders in humans and interfering with their degradation would be a treatment option, but it remains out of reach due to limited knowledge. The plasmalogen double bond is degraded either directly by a plasmalogenase or by conversion to the 2' lyso forms by phospholipase and subsequent cleavage by lysoplasmalogenase (E.C. 3.3.2.2). Two lysoplasmalogenases are known so far, TMEM86A and TMEM86B. While TMEM86B has been expressed in bacteria, purified, and shown to encode lysoplasmalogenase activity by a coupled optical assay, the closely related protein TMEM86A has not yet been purified, but its activity was shown indirectly by a lipidomics approach. Here, we present a novel assay for lysoplasmalogenase activity based on incubation with lysoplasmenylethanolamine or lysoplasmenylcholine, derivatization of the aldehyde product with dansylhydrazine, and hydrazone quantification by reversed-phase HPLC with fluorescence detection. The method was sensitive enough to robustly detect lysoplasmalogenase activity in human embryonic kidney cells following transient expression of TMEM86A or TMEM86B and also suitable for the determination of lysoplasmalogenase activity in mouse tissues where highest activities were found in liver and duodenum. We introduced point mutations at positions proposed to be catalytically relevant and provided experimental evidence that all but one affected lysoplasmalogenase activity. Our novel assay allows direct and fast measurement of lysoplasmalogenase activity, thereby providing a tool to advance research in the field of plasmalogen degradation.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100766"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11994398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purifying selection of the lysosomal enzymes arylsulfatase A and beta-galactocerebrosidase and their evolutionary impact on myelin integrity.","authors":"Matthew A Luetzen, Richik Chakraborty, Oscar Andrés Moreno-Ramos, Olga Yaneth Echeverri-Peña, Yoko Satta, Adriana M Montaño","doi":"10.1016/j.jlr.2025.100769","DOIUrl":"10.1016/j.jlr.2025.100769","url":null,"abstract":"<p><p>The myelin is responsible for providing stability to the axons of the nerve cells, but above all, to improve transmission speed of the nerve impulse in vertebrates. Over 70% of the myelin sheath is composed of lipids and the remaining portion by approximately 2,000 proteins. The myelin sheath has been constantly evolving, and it is known that unusually high concentrations of galactosylceramide (GalCer) and its sulfated form play a major role in the biophysical properties of the myelin. To gain insights of the evolutionary role of GalCer, we have studied two lysosomal enzymes involved in GalCer degradation, arylsulfatase A (ARSA) and galactocerebrosidase (GALC). Deficiency of ARSA or GALC causes demyelinating disorders. We conducted phylogenetic analyses of 105 ARSA and 110 GALC orthologs representing more than 600 million years ago of evolution. We examined i) low values of the ratio of nonsynonymous to synonymous nucleotide-substitution rates (dN/dS) indicating purifying selection and ii) negative selection of amino acids located in the active site preventing pathogenic mutations. Gene structure analyses showed evidence of rearrangement with gain and loss of exons while there were conserved regions mainly located around the active site. We also found a limited number of sites under positive selection pressure that do not cause alterations to the overall protein structure. Our results indicate that ARSA and GALC have been highly conserved during the evolutionary process to maintain the metabolism of GalCer, which is essential for the integrity of the white matter in vertebrate species.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100769"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphatidylcholine synthesis and remodeling in brain endothelial cells.","authors":"Mohamed H Yaghmour, Theja Sajeevan, Christoph Thiele, Lars Kuerschner","doi":"10.1016/j.jlr.2025.100773","DOIUrl":"10.1016/j.jlr.2025.100773","url":null,"abstract":"<p><p>Mammalian cells synthesize hundreds of different variants of their prominent membrane lipid phosphatidylcholine (PC), all differing in the side chain composition. This batch is constantly remodeled by the Lands cycle, a metabolic pathway replacing one chain at a time. Using the alkyne lipid lyso-phosphatidylpropargylcholine (LpPC), a precursor and intermediate in PC synthesis and remodeling, we study both processes in brain endothelial bEND3 cells. A novel method for multiplexed sample analysis by mass spectrometry is developed that offers high throughput and molecular species resolution of the propargyl-labeled PC lipids. Their time-resolved profiles and kinetic parameters of metabolism demonstrate the plasticity of the PC pool and the acute handling of lipid influx in endothelial cells differs from that in hepatocytes. Side chain remodeling as a form of lipid cycling adapts the PC pool to the cell's need and maintains lipid homeostasis. We estimate that endothelial cells possess the theoretical capacity to remodel up to 99% of their PC pool within 3.5 h using the Lands cycle. However, PC species are not subjected stochastically to this remodeling pathway as different species containing duplets of saturated, omega-3, and omega-6 side chains show different decay kinetics. Our findings emphasize the essential function of Lands cycling for monitoring and adapting the side chain composition of PC in endothelial cells.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100773"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered liver lipidome markedly overlaps with human plasma lipids at diabetes risk and reveals adipose-liver interaction.","authors":"Ratika Sehgal, Markus Jähnert, Michail Lazaratos, Thilo Speckmann, Fabian Schumacher, Burkhard Kleuser, Meriem Ouni, Wenke Jonas, Annette Schürmann","doi":"10.1016/j.jlr.2025.100767","DOIUrl":"10.1016/j.jlr.2025.100767","url":null,"abstract":"<p><p>Present study explores the role of liver lipidome in driving T2D-associated metabolic changes. Elevated liver triacylglycerols, reduced PUFAs, and 86 differentially abundant lipid species were identified in diabetes-prone mice. Of these altered lipid species, 82 markedly overlap with human plasma lipids associated with T2D/CVD risk. Pathway enrichment highlighted sphingolipid metabolism, however, only five of all genes involved in the pathway were differentially expressed in the liver. Interestingly, overlap with adipose tissue transcriptome was much higher (57 genes), pointing toward an active adipose-liver interaction. Next, the integration of liver lipidome and transcriptome identified strongly correlated lipid-gene networks highlighting ceramide [Cer(22:0)], dihydroceramide(24:1), and triacylglycerol(58:6) playing a central role in transcriptional regulation. Putative molecular targets of Cer(22:0) were altered (Cyp3a44, Tgf-β1) in primary mouse hepatocytes treated with Cer(22:0). Early alteration of liver lipidome markedly depends on adipose tissue expression pattern and provides substantial evidence linking early liver lipidome alterations and risk of T2D.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100767"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity.","authors":"Weinan Zhou, Sarith R Bandara, Kyungwon Ko, Oludemilade Akinrotimi, Diego Hernández-Saavedra, Emily Richter, Noah Brauer, Taylor J Woodward, Heather B Bradshaw, Cecilia Leal, Sayeepriyadarshini Anakk","doi":"10.1016/j.jlr.2025.100754","DOIUrl":"10.1016/j.jlr.2025.100754","url":null,"abstract":"<p><p>The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high-fat diet (HFD)-fed control mice. Moreover, upon HFD challenge, these effects are worsened in adipocyte-specific Fxr knockout mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that Faah inhibition or deletion is linked to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100754"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cadmium-cardiolipin disruption of respirasome assembly and redox balance through mitochondrial membrane rigidification.","authors":"Nadiya Romanova, Kevin Sule, Travis Issler, Daniel Hebrok, Marcus Persicke, Frank Thévenod, Elmar J Prenner, Wing-Kee Lee","doi":"10.1016/j.jlr.2025.100750","DOIUrl":"10.1016/j.jlr.2025.100750","url":null,"abstract":"<p><p>The environmental pollutant cadmium (Cd) poses a threat to human health through the consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface), and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40 mol % POPC, 35 mol % DOPE, 20 mol % TOCL, 5 mol % SAPI) nanoliposomes were rigidified by 25 μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III₂+IV_n SC formation after 5 μM Cd for 6 h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1 μM), yet α-tocopherol-insensitive. Moreover, MTP-131 attenuated Cd-induced H₂O₂ (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5 μM, 24 h) cytotoxicity (∼25%) by MTT assay, Cd (5 μM, 3 h)-induced ROS and mitochondrial membrane rigidification by Cd (1 μM, 1 h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100750"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}