Deficiency in Sphingosine-1-Phosphate Lyase (S1P lyase) is associated with a multi-systemic disorder incorporating primary adrenal insufficiency (PAI), steroid resistant nephrotic syndrome and neurological dysfunction. Accumulation of sphingolipid intermediates, as seen with loss of function mutations in SGPL1, has been implicated in mitochondrial dysregulation, including alterations in mitochondrial membrane potentials and initiation of mitochondrial apoptosis. For the first time, we investigate the impact of S1P lyase deficiency on mitochondrial morphology and function using patient-derived human dermal fibroblasts and CRISPR engineered SGPL1-knockout HeLa cells. Reduced cortisol output in response to progesterone stimulation was observed in two patient dermal fibroblast cell lines. Mass spectrometric analysis of patient dermal fibroblasts revealed significantly elevated levels of sphingosine-1-phosphate, sphingosine, ceramide species and sphingomyelin when compared to control. Total mitochondrial volume was reduced in both S1P lyase deficient patient and HeLa cell lines. Mitochondrial dynamics and parameters of oxidative phosphorylation were altered when compared to matched controls, though differentially across the cell lines. Mitochondrial dysfunction may represent a major event in the pathogenesis of this disease, associated with severity of phenotype.

鞘氨醇-1-磷酸裂解酶（S1P裂解酶）的缺乏与多系统疾病有关，合并了原发性肾上腺功能不全（PAI），类固醇抵抗性肾病综合征和神经功能障碍。如SGPL1中功能突变的丧失所见，鞘脂中间体的积累与线粒体失调有关，包括线粒体膜电位的改变和线粒体凋亡的启动。首次，我们使用患者衍生的人真皮成纤维细胞和CRISPR工程SGPL1研究S1P裂解酶缺乏对线粒体形态和功能的影响-敲除HeLa细胞。在两个患者的真皮成纤维细胞系中观察到了响应孕激素刺激的皮质醇输出减少。对患者皮肤成纤维细胞的质谱分析显示，与对照组相比，鞘氨醇-1-磷酸，鞘氨醇，神经酰胺和鞘磷脂水平显着升高。S1P裂解酶缺陷患者和HeLa细胞系的总线粒体体积均减少。与匹配的对照相比，线粒体动力学和氧化磷酸化参数发生了变化，尽管在整个细胞系中差异很大。线粒体功能障碍可能是该病发病机制中的主要事件，与表型的严重程度有关。