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Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with ?-cell failure.

ABSTRACT: OBJECTIVE:Diabetes is characterized by pancreatic ?-cell dedifferentiation. Dedifferentiating ? cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the ?-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear. METHODS:Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to ?-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios. RESULTS:The expression of Cyb5r3 is decreased in FoxO1-deficient ? cells. Mice with ?-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient ? cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient ? cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability. CONCLUSIONS:The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate ?-cell failure.

SUBMITTER: Fan J

PROVIDER: S-EPMC7031142 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure.

Fan Jason J Du Wen W Kim-Muller Ja Young JY Son Jinsook J Kuo Taiyi T Larrea Delfina D Garcia Christian C Kitamoto Takumi T Kraakman Michael J MJ Owusu-Ansah Edward E Cirulli Vincenzo V Accili Domenico D

Molecular metabolism 20200204

<h4>Objective</h4>Diabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear.<h4>Methods</h4>Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/se ...[more]

PMID: 32180563

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Project description:PurposeCell death is an essential process in normal development and homeostasis. In eyes, corneal epithelial injury leads to the death of cells in underlying stroma, an event believed to initiate corneal wound healing. The molecular basis of wound induced corneal stromal cell death is not understood in detail. Studies of others have indicated that ceramide may play significant role in stromal cell death following LASIK surgery. We have undertaken the present study to investigate the mechanism of death induced by C6 ceramide in cultures of human corneal stromal (HCSF) fibroblasts.MethodsCultures of HCSF were established from freshly excised corneas. Cell death was induced in low passage (p<4) cultures of HCSF by treating the cells with C6 ceramide or C6 dihydroceramide as a control. Cell death was assessed by Live/Dead cell staining with calcein AM and ethidium homodimer-1 as well as Annexin V staining, caspase activation and TUNEL staining Mitochondrial dysfunction was assessed by Mito Sox Red, JC-1 and cytochrome C release Gene expression was examined by qPCR and western blotting.ResultsOur data demonstrate ceramide caused mitochondrial dysfunction as evident from reduced MTT staining, cyto c release from mitochondria, enhanced generation of ROS, and loss in mitochondrial membrane potential (??m). Cell death was evident from Live -Dead Cell staining and the inability to reestablish cultures from detached cells. Ceramide induced the expression of the harikari gene(HRK) and up-regulated JNK phosphorylation. In ceramide treated cells HRK was translocated to mitochondria, where it was found to interact with mitochondrial protein p32. The data also demonstrated HRK, p32 and BAD interaction. Ceramide-induced expression of HRK, mitochondrial dysfunction and cell death were reduced by HRK knockdown with HRK siRNA.ConclusionOur data document that ceramide is capable of inducing death of corneal stromal fibroblasts through the induction of HRK mediated mitochondria dysfunction.

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Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with ?-cell failure.

Publications

Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure.

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