Cargando…
Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure
OBJECTIVE: 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...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031142/ https://www.ncbi.nlm.nih.gov/pubmed/32180563 http://dx.doi.org/10.1016/j.molmet.2019.12.008 |
_version_ | 1783499311532736512 |
---|---|
author | Fan, Jason Du, Wen Kim-Muller, Ja Young Son, Jinsook Kuo, Taiyi Larrea, Delfina Garcia, Christian Kitamoto, Takumi Kraakman, Michael J. Owusu-Ansah, Edward Cirulli, Vincenzo Accili, Domenico |
author_facet | Fan, Jason Du, Wen Kim-Muller, Ja Young Son, Jinsook Kuo, Taiyi Larrea, Delfina Garcia, Christian Kitamoto, Takumi Kraakman, Michael J. Owusu-Ansah, Edward Cirulli, Vincenzo Accili, Domenico |
author_sort | Fan, Jason |
collection | PubMed |
description | OBJECTIVE: 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. METHODS: Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-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 β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β 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 β 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 β-cell failure. |
format | Online Article Text |
id | pubmed-7031142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-70311422020-02-25 Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure Fan, Jason Du, Wen Kim-Muller, Ja Young Son, Jinsook Kuo, Taiyi Larrea, Delfina Garcia, Christian Kitamoto, Takumi Kraakman, Michael J. Owusu-Ansah, Edward Cirulli, Vincenzo Accili, Domenico Mol Metab Original Article OBJECTIVE: 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. METHODS: Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-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 β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β 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 β 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 β-cell failure. Elsevier 2020-02-04 /pmc/articles/PMC7031142/ /pubmed/32180563 http://dx.doi.org/10.1016/j.molmet.2019.12.008 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Fan, Jason Du, Wen Kim-Muller, Ja Young Son, Jinsook Kuo, Taiyi Larrea, Delfina Garcia, Christian Kitamoto, Takumi Kraakman, Michael J. Owusu-Ansah, Edward Cirulli, Vincenzo Accili, Domenico Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure |
title | Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure |
title_full | Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure |
title_fullStr | Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure |
title_full_unstemmed | Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure |
title_short | Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure |
title_sort | cyb5r3 links foxo1-dependent mitochondrial dysfunction with β-cell failure |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031142/ https://www.ncbi.nlm.nih.gov/pubmed/32180563 http://dx.doi.org/10.1016/j.molmet.2019.12.008 |
work_keys_str_mv | AT fanjason cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT duwen cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT kimmullerjayoung cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT sonjinsook cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT kuotaiyi cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT larreadelfina cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT garciachristian cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT kitamototakumi cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT kraakmanmichaelj cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT owusuansahedward cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT cirullivincenzo cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure AT accilidomenico cyb5r3linksfoxo1dependentmitochondrialdysfunctionwithbcellfailure |