Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction

The Journal of Steroid Biochemistry and Molecular Biology
Avinaash MaharajRathi Prasad

Abstract

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 lin...Continue Reading

Methods Mentioned

BETA
biopsies
ELISA
protein assay
fluorescence microscopy
confocal microscopy
GTPase

Key Resources (RRID) Mentioned

AB_2160739
AB_2629281
AB_398423
AB_2188674
AB_307275
AB_2223210
AB_10793856
AB_10796098
AB_2651128
AB_2721181

Software Mentioned

Imaris
LI−COR Image Studio
ImarisSurface

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis