Lysophosphatidylcholine acyltransferase 1 controls the mitochondrial reactive oxygen species generation and survival of the retinal photoreceptor cells

Due to the 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 with a frameshift mutation of lysophosphatidylcholine acyltransferase 1 ( Lpcat1 ), which produces saturated phosphatidylcholine (PC) composed of two saturated fatty acids, has been reported to cause spontaneous retinal degeneration ( rd 11 mice). 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 decreases saturated PC production and affects 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 saturated 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. ### Competing Interest Statement The Department of Lipid Signaling, National Center for Global Health and Medicine, is financially supported by ONO Pharmaceutical Co., Ltd.. * AGPAT3 : 1-acylglycerol-3-phosphate O -acyltransferase 3 AMD : age-related macular degeneration ANOVA : analysis of variance AP-1 : Activator protein-1 CHOP : CCAAT-enhancer-binding protein homologous protein CNG : cyclic nucleotide-gated Crb1 : Crumbs homolog 1 DAVID : The Database for Annotation Visualization and Integrated Discovery DEGs : differentially expressed genes DHA : docosahexaenoic acid DPPC : dipalmitoyl PC ER : endoplasmic reticulum FA : fatty acid GCL : ganglion cell layer GO : gene ontology HZ : heterozygote IEGs : immediate early genes INL : inner nuclear layer KO : knockout LPAAT3 : lysophosphatidic acid acyltransferase 3 LPC : lysophosphatidylcholine LPCAT1 : lysophosphatidylcholine acyltransferase 1 LPLATs : lysophospholipid acyltransferases MRM : multiple reaction monitoring ONL : outer nuclear layer OS : outer segment P8 : postnatal day 8 PC : phosphatidylcholine PDE6β : phosphodiesterase 6β PUFA : polyunsaturated FA rd : retinal degeneration ROS : reactive oxygen species RPE : retinal pigment epithelial SCD : stearoyl-CoA desaturase SFA : saturated FA SM : sphingomyelin SRM : selected reaction monitoring TEM : transmitted electron microscopy TUNEL : terminal deoxynucleotidyl transferase dUTP nick-end labeling.