中山大学学报（医学科学版）2026，Vol.47Issue(4)：656-669,14.DOI:10.11714/jsysu.med.YX20260032
光感受器Lss缺失通过线粒体功能障碍与氧化应激导致年龄相关性视网膜退行性病变
Lanosterol Synthase Deficiency in Photoreceptor Leads to Age-related Retinal Degeneration via Mitochondrial Dysfunction and Oxidative Stress
摘要
Abstract
[Objective]To investigate whether photoreceptor-specific knockout of lanosterol synthase(Lss)induces age-related retinal degeneration and to elucidate the underlying molecular mechanisms.[Methods]Photoreceptor-specific Lss knockout mice(Lssflox/flox;Rho-Cre,CKO)models were established.Retinal structure and function were assessed at 1,4,and 8 months of age using fundus photography,optical coherence tomography (OCT),scotopic electroretinogram (ERG) and hematoxylin and eosin (HE) staining. The mouse photoreceptor cell line 661W served as an in vitro model. Lss was knocked down via siRNA,followed by analyses including Seahorse XF mitochondrial stress test,JC-1,MitoSOX Red and DCFH-DA probes to evaluate mitochondrial function and oxidative stress,glycolytic rate assay for glycolysis ability,RT-qPCR for inflammatory factors,γH2AX immunofluorescence for double-strand DNA damage detection,and transcriptome sequencing to identify differentially expressed genes and enriched pathways.[Results]Compared with controls,1-month-old CKO mice showed no abnormalities. Mild fundus lesions appeared at 4 months. By 8 months,CKO mice exhibited significant thinning of the outer nuclear layer,disorganization of the inner/outer segment structure,and markedly reduced amplitudes of the dark-adapted ERG a-and b-waves (P<0.05). Transcriptome analysis revealed 1 842 differentially expressed genes (826 up-regulated,1 016 down-regulated),with Lss being the most significantly downregulated gene;these genes significantly enriched in sterol biosynthesis,oxidative phosphorylation,aerobic electron transport chain,and ATP synthesis (P<0.05). In 661W cells,knockdown of Lss significantly reduced mitochondrial basal respiration (P=0.006),ATP production (P=0.015),maximal respiration (P<0.001),and spare respiratory capacity (P<0.001),while basal glycolysis (P=0.005) and compensatory glycolysis (P=0.028) were increased. These changes were accompanied by mitochondrial membrane potential depolarization (P<0.001),elevated mitochondrial reactive oxygen species (ROS) levels (P<0.001),and increased total ROS levels (P=0.013). Additionally,the mRNA expression of inflammatory factors,including Ccl2 (P=0.004),Ccl5 (P=0.012),Cxcl1 (P<0.001),Cxcl5 (P<0.000 1),Tgfb (P=0.008),Hgf (P<0.000 1) and Mmp3 (P=0.003) was significantly upregulated. Moreover,γH2AX fluorescence intensity was increased (P=0.002).[Conclusions]Photoreceptor-specific Lss deficiency induces mitochondrial dysfunction,oxidative stress and cellular inflammation,ultimately leading to age-dependent retinal degeneration. This study provides novel mechanistic insights and potential therapeutic targets for hereditary and age-related retinal degenerative diseases.关键词
羊毛甾醇合成酶/光感受器/视网膜退行性疾病/线粒体功能障碍/氧化应激Key words
lanosterol synthase/photoreceptor/retinal degeneration/mitochondrial dysfunction/oxidative stress分类
医药卫生引用本文复制引用
杨浩涵,罗淑茜,陈海琪,黎韦华,赵凌..光感受器Lss缺失通过线粒体功能障碍与氧化应激导致年龄相关性视网膜退行性病变[J].中山大学学报（医学科学版）,2026,47(4):656-669,14.基金项目
国家自然科学基金(32270621,81721003) （32270621,81721003）
广州市校市联合基金(2023A03J0186) （2023A03J0186）
眼病防治全国重点实验室课题基金(2025QZSPT36) （2025QZSPT36）
