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

A Maharaj,J Williams,T Bradshaw,T Güran,D Braslavsky,J Casas,L.F Chan,L.A Metherell,R Prasad

doi:10.1016/j.jsbmb.2020.105730

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 lines. Mitochondrial dysfunction may represent a major event in the pathogenesis of this disease, associated with severity of phenotype.

Highlights

Sphingolipids are ubiquitous structural components of mammalian plasma membranes whose roles have been implicated in signal transduction and cellular recognition pathways [1]
Sphingosine-1-phosphate lyase insufficiency represents a clinically heterogeneous condition, with the majority of mutations reported in single families and variability in phenotype seen even with the same mutation
Fibroblast cell cultures were established from two affected individuals [4] with adrenal failure and steroid resistant nephrotic syndrome (SRNS), FIB_545del, from patient 1 with p.F545del (c.1633_1635delTTC, an in-frame deletion) and FIB_65fs, from patient 2 with p.S65Nfs*11 (c.261 + 1G > A, a canonical splice-site change), each mutation has only been reported in a single family

Summary

Introduction

Sphingolipids are ubiquitous structural components of mammalian plasma membranes whose roles have been implicated in signal transduction and cellular recognition pathways [1]. S1P lyase (SGPL1) is a pyridoxal 5’-phosphate-dependent aldehydelyase (encoded by the gene SGPL1) which binds sphingosine 1-phosphate (S1P) and catalyses the final and irreversible degradative step in sphingolipid metabolism forming phosphoethanolamine and the long chain aldehyde, hexadecanal (Fig. 1). Up until this point in the pathway enzyme reactions are reversible, S1P lyase is a major modulator of total cellular sphingolipid intermediates and S1P signalling. In 2017, Prasad et al [4], Lovric et al [5] and Janecke et al [6], described a series of patients with loss of function mutations in SGPL1 and a novel syndrome

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