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

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dc.contributor.authorGÜRAN, TÜLAY
dc.contributor.authorsMaharaj, A.; Williams, J.; Bradshaw, T.; Guran, T.; Braslavsky, D.; Casas, J.; Chan, L. F.; Metherell, L. A.; Prasad, R.
dc.date.accessioned2022-03-14T09:29:25Z
dc.date.available2022-03-14T09:29:25Z
dc.date.issued2020-09
dc.description.abstractDeficiency 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.
dc.identifier.doi10.1016/j.jsbmb.2020.105730
dc.identifier.issn0960-0760
dc.identifier.pubmed32682944
dc.identifier.urihttps://hdl.handle.net/11424/243187
dc.identifier.wosWOS:000568822300004
dc.language.isoeng
dc.publisherPERGAMON-ELSEVIER SCIENCE LTD
dc.relation.ispartofJOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectSphingolipid metabolism
dc.subjectMitochondrial dynamics
dc.subjectSteroidogenic capacity
dc.subjectOxidative phosphorylation
dc.subjectSphingosine-1-phosphate lyase
dc.subjectADRENAL INSUFFICIENCY
dc.subjectSPHINGOSINE 1-PHOSPHATE
dc.subjectNEPHROTIC SYNDROME
dc.subjectEXPRESSION
dc.subjectMUTATIONS
dc.subjectRECEPTOR
dc.subjectFUSION
dc.subjectCORTICOSTERONE
dc.subjectSPHINGOLIPIDS
dc.subjectBIOSYNTHESIS
dc.titleSphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction
dc.typearticle
dspace.entity.typePublication
local.avesis.id2c3ebc9e-d6e2-464c-945c-27ddf47ad0f3
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.articlenumber105730
local.journal.numberofpages12
local.journal.quartileQ2
oaire.citation.titleJOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
oaire.citation.volume202
relation.isAuthorOfPublicationcd5bac46-bf24-476a-80cb-1cea576c283a
relation.isAuthorOfPublication.latestForDiscoverycd5bac46-bf24-476a-80cb-1cea576c283a

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