Lysophosphatidylcholine acyltransferase 1 controls the mitochondrial reactive oxygen species generation and survival of the retinal photoreceptor cells [2w Retina]
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PROVIDER: PRJNA766600 | ENA |
REPOSITORIES: ENA
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Project description:Due to the high energy demands and characteristic morphology, retinal photoreceptor cells require the specialized lipid metabolism for survival and functions. In this study, we focus on the roles of saturated fatty acids and their metabolism in these processes. Frame-shift mutation of lysophosphatidylcholine acyltransferase 1 (Lpcat1), which introduces saturated fatty acid into lysophosphatidylcholine to produce disaturated phosphatidylcholine (PC), has been reported as a causative for spontaneous retinal degeneration in mice (rd11 mice). However, the molecular basis of retinal degeneration caused by Lpcat1 mutation remains unclear. Here, we report that Lpcat1 deficiency induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 affects not only disaturated PC production, but also the proper cellular fatty acid flux presumably through altering saturated fatty acyl-CoA availabilities. Furthermore, we demonstrated that Lpcat1 deletion increased mitochondrial reactive oxygen species (ROS) levels in photoreceptor cells, but not in other retinal cells, without affecting the OS structure and trafficking of OS localized proteins. These results suggested that LPCAT1-dependent production of disaturated PC is critical for metabolic adaptation during photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.
2022-01-01 | GSE184815 | GEO
Project description:Due to the high energy demands and characteristic morphology, retinal photoreceptor cells require a specialized lipid metabolism for survival and function. This study focused on the roles of saturated fatty acids and their metabolism. A frameshift mutation of lysophosphatidylcholine acyltransferase 1 (Lpcat1), introducing saturated fatty acids into lysophosphatidylcholine to produce disaturated phosphatidylcholine (PC), has been reported to cause spontaneous retinal degeneration in mice (rd11 mice). In this study, we performed a detailed characterization of Lpcat1 in the retina and found that Lpcat1 deficiency induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of the retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 affects disaturated PC production and the proper cellular fatty acid flux, presumably by altering saturated fatty acyl-CoA availabilities. Furthermore, we demonstrated that Lpcat1 deletion increased mitochondrial reactive oxygen species (ROS) levels in photoreceptor cells, but not in other retinal cells without affecting the OS structure and trafficking of OS-localized proteins. These results suggest that the LPCAT1-dependent production of disaturated PC is critical for metabolic adaptation during photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.
2022-01-01 | GSE184817 | GEO
Project description:Lysophosphatidylcholine acyltransferase 1 controls the mitochondrial reactive oxygen species generation and survival of the retinal photoreceptor cells [P8 photoreceptor]
| PRJNA766601 | ENA
Project description:Lysophosphatidylcholine acyltransferase 1 controls the mitochondrial reactive oxygen species generation and survival of the retinal photoreceptor cells
| PRJNA766595 | ENA
Project description:Due to their high energy demands and characteristic morphology, retinal photoreceptor cells require a specialized lipid metabolism for survival and function. Accordingly, dysregulation of lipid metabolism leads to the photoreceptor cell death and retinal degeneration. Mice bearing a frameshift mutation in the gene encoding lysophosphatidylcholine acyltransferase 1 (Lpcat1), which produces saturated phosphatidylcholine (PC) composed of two saturated fatty acids, has been reported to cause spontaneous retinal degeneration in mice; however, the mechanism by which this mutation affects degeneration is unclear. In this study, we performed a detailed characterization of LPCAT1 in the retina and found that genetic deletion of Lpcat1 induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of the retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 not only decreased saturated PC production but also affected membrane lipid composition, presumably by altering saturated fatty acyl-CoA availability. Furthermore, we demonstrated that Lpcat1 deletion led to increased mitochondrial reactive oxygen species levels in photoreceptor cells, but not in other retinal cells, and did not affect the OS structure or trafficking of OS-localized proteins. These results suggest that the LPCAT1-dependent production of saturated PC plays critical roles in photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.
| S-EPMC9136105 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-01-01 | GSE184818 | GEO
Project description:Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are a leading cause of untreatable blindness with substantive impact on the quality of life of affected individuals and their families. Mouse mutants with retinal dystrophies have provided a valuable resource to discover human disease genes and helped uncover pathways critical for photoreceptor function. Here we show that the rd11 mouse mutant and its allelic strain, B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by degeneration of both rods and cones. Using linkage analysis, we mapped the rd11 locus to mouse chromosome 13. We then identified a one-nucleotide insertion (c.420-421insG) in exon 3 of the Lpcat1 gene. Subsequent screening of this gene in the B6-JR2845 strain revealed a seven-nucleotide deletion (c.14-20delGCCGCGG) in exon 1. Both sequence changes are predicted to result in a frame-shift, leading to premature truncation of the lysophosphatidylcholine acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoylphosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 and B6-JR2845 mice showed substantially reduced DPPC levels compared with C57BL/6J control mice, suggesting a causal link to photoreceptor dysfunction. A follow-up screening of LPCAT1 in retinitis pigmentosa and Leber congenital amaurosis patients did not reveal any obvious disease-causing mutations. Previously, LPCAT1 has been suggested to be critical for the production of lung surfactant phospholipids and biosynthesis of platelet-activating factor in noninflammatory remodeling pathway. Our studies add another dimension to an essential role for LPCAT1 in retinal photoreceptor homeostasis.
| S-EPMC2932565 | biostudies-literature
Project description:OBJECTIVE:Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here, we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. APPROACH AND RESULTS:Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0, and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout mice during early atherosclerosis. Using electron spin resonance and flow cytometry, we found that LPC 16:0, 18:0, and 18:1 induced mtROS in primary human aortic ECs, independently of the activities of nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, using confocal microscopy and Seahorse XF mitochondrial analyzer, we showed that LPC induced mtROS via unique calcium entry-mediated increase of proton leak and mitochondrial O2 reduction. In addition, we found that mtROS contributed to LPC-induced EC activation by regulating nuclear binding of activator protein-1 and inducing intercellular adhesion molecule-1 gene expression in vitro. Furthermore, we showed that mtROS inhibitor MitoTEMPO suppressed EC activation and aortic monocyte recruitment in apolipoprotein E knockout mice using intravital microscopy and flow cytometry methods. CONCLUSIONS:ATP synthesis-uncoupled, but proton leak-coupled, mtROS increase mediates LPC-induced EC activation during early atherosclerosis. These results indicate that mitochondrial antioxidants are promising therapies for vascular inflammation and cardiovascular diseases.
| S-EPMC4882253 | biostudies-literature
Project description:The mammalian RBC lacks de novo lipid synthesis but maintains its membrane composition by rapid turnover of acyl moieties at the sn-2 position of phospholipids. Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. These proteins are three members of a LPCAT family, of which all three genes are expressed in an erythroleukemic cell line. Aytl2 mRNA was detected in mouse reticulocytes, and the presence of the product of the human ortholog was confirmed in adult human RBCs. The three murine Aytl proteins generated phosphatidylcholine from long-chain acyl-CoA and lysoPC when expressed in Escherichia coli membranes. Spliced variants of Aytl1, affecting a conserved catalytic motif, were identified. Calcium and magnesium modulated LPCAT activity of both Aytl1 and -2 proteins that exhibit EF-hand motifs at the C terminus. Characterization of the product of the Aytl2 gene as the phosphatidylcholine reacylating enzyme in RBCs represents the identification of a plasma membrane lysophospholipid acyltransferase and establishes the function of a LPCAT protein.
| S-EPMC2224237 | biostudies-literature
Project description:The gene expression patterns in the medial prefrontal cortex of wild-type mice (2W and 12W) were examined using Affymetrix GeneChip arrays.
2019-02-25 | GSE118667 | GEO