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.

1-磷酸鞘氨醇裂解酶（S1P 裂解酶）缺乏与多系统疾病相关，包括原发性肾上腺皮质功能不全 (PAI)、类固醇抵抗性肾病综合征和神经功能障碍。鞘脂中间体的积累（如SGPL1 功能缺失突变所示）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。我们首次使用患者来源的人真皮成纤维细胞和 CRISPR 工程改造的SGPL1敲除 HeLa 细胞研究 S1P 裂解酶缺陷对线粒体形态和功能的影响。在两个患者真皮成纤维细胞系中观察到黄体酮刺激导致的皮质醇输出减少。对患者真皮成纤维细胞的质谱分析显示，与对照相比，1-磷酸鞘氨醇、鞘氨醇、神经酰胺种类和鞘磷脂的水平显着升高。 S1P 裂解酶缺陷患者和 HeLa 细胞系的线粒体总体积均减少。与匹配对照相比，线粒体动力学和氧化磷酸化参数发生了改变，尽管在细胞系之间存在差异。线粒体功能障碍可能是该疾病发病机制中的一个主要事件，与表型的严重程度相关。