Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation

Abstract

BackgroundEmerging 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).MethodsWe 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.ResultsLack 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.ConclusionAltogether, 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.

Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

“…The effect of FP on mitochondrial function could be related to the modulation of mitochondrial translocator protein expression (TSPO) [ 36 ], a mitochondrial membrane protein associated with the mitochondrial permeability pore that is expressed in all cells of embryonic origin [ 37 ], such as those used in this work; this has been seen in MS, where FP decreases the expression of TSPO [ 38 ], stabilizing mitochondria. Furthermore, we could not exclude the possibility that PF may regulate the expression of prohibitins, a chaperone that regulates the mitochondrial respiratory complex assembly and activity [ 39 , 40 , 41 , 42 ]. There are also some reports on the protective effect of the stimulation of S1P1 receptor on genes involved in the expression of proteins that participate in the stabilization of mitochondrial function [ 36 ].…”

Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction

“…Additionally, Hong et al. observed both decreased insulin secretion and reduced cell survival when Min6 cells were treated with 15 μM SKI for 48 h ( Hong et al., 2018 ). In the case of sphingomyelin biosynthesis, Subathra et al.…”

Involvement of miR‐27a‐3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress

“…According to a previous study, miR‐27a is upregulated in hypoxia‐induced mitochondrial dysfunction in the murine preadipocyte cell line (Marques et al, 2017). Deficiency of prohibitin has been demonstrated to induce mitochondrial dysfunction in mouse insulinoma 6 cells (Hong et al, 2018). It was also corroborated that miR‐27a targets prohibitin and impairs mitochondrial function in human adipose‐derived stem cells (Kang et al, 2013).…”