Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation.
10.3803/EnM.2018.33.3.403
- Author:
Seok Woo HONG
1
;
Jinmi LEE
;
Hyemi KWON
;
Se Eun PARK
;
Eun Jung RHEE
;
Cheol Young PARK
;
Ki Won OH
;
Sung Woo PARK
;
Won Young LEE
Author Information
1. Institute of Medical Research, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
- Publication Type:Original Article
- Keywords:
Sphingosine 1-phosphate;
Sphingosine kinase;
Insulin-secreting cells;
Mitochondria;
Prohibitin
- MeSH:
Adenosine Triphosphate;
Animals;
Apoptosis;
GTP Phosphohydrolases;
Insulin;
Insulin-Secreting Cells;
Insulinoma;
Membrane Potential, Mitochondrial;
Metabolism;
Mice;
Mitochondria;
Mitochondrial Dynamics;
Oxidative Phosphorylation;
Oxygen Consumption;
Phosphotransferases;
Repression, Psychology;
RNA, Small Interfering;
Sphingolipids;
Sphingosine
- From:Endocrinology and Metabolism
2018;33(3):403-412
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND: Emerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB). METHODS: We examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels. RESULTS: Lack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends. CONCLUSION: Altogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.
