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

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Sphingosine-1-phosphate lyase (S1P lyase) deficiency is linked to a multi-system disorder including primary adrenal insufficiency (PAI), nephrotic syndrome, and neurological issues.
• Loss-of-function mutations in SGPL1 cause sphingolipid intermediate accumulation, implicated in mitochondrial dysregulation and apoptosis.
• Previous research suggests sphingolipid accumulation impacts mitochondrial health, but direct investigation into morphology and function in S1P lyase deficiency is lacking.

Purpose of the Study:

• To investigate the impact of S1P lyase deficiency on mitochondrial morphology and function.
• To analyze sphingolipid profiles and cortisol output in patient-derived cells.
• To compare mitochondrial alterations in patient cells and engineered SGPL1-knockout cells.

Main Methods:

• Utilized patient-derived human dermal fibroblasts and CRISPR-engineered SGPL1-knockout HeLa cells.
• Performed mass spectrometry to quantify sphingolipid levels.
• Assessed mitochondrial volume, dynamics, and oxidative phosphorylation parameters.

Main Results:

• Patient fibroblasts showed reduced cortisol output upon progesterone stimulation.
• Elevated levels of sphingosine-1-phosphate, sphingosine, ceramides, and sphingomyelin were detected in patient cells.
• Both patient and knockout cell lines exhibited reduced total mitochondrial volume and altered mitochondrial dynamics and oxidative phosphorylation.

Conclusions:

• S1P lyase deficiency leads to significant alterations in mitochondrial morphology and function.
• Mitochondrial dysfunction is a key factor in the pathogenesis of S1P lyase deficiency disorders.
• These mitochondrial changes correlate with disease severity, highlighting their pathogenic role.