Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with ß-cell failure.
Mol Metab
; 34: 97-111, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-32180563
ABSTRACT
OBJECTIVE:
Diabetes is characterized by pancreatic ß-cell dedifferentiation. Dedifferentiating ß cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the ß-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 ß-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 ß cells. Mice with ß-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient ß 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 ß 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 ß-cell failure.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Citocromo-B(5) Redutase
/
Células Secretoras de Insulina
/
Proteína Forkhead Box O1
/
Mitocôndrias
Limite:
Animals
Idioma:
En
Revista:
Mol Metab
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos