ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis
| Autor: | Kailiang Zhang, Rong Bao, Fengyuan Huang, Kevin Yang, Qinqiang Long, Lothar Lauterboeck, Qinglin Yang, Yishu Ding, Masasuke Yoshida |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Cellular respiration
medicine.medical_treatment Protein subunit Mice Transgenic Oxidative phosphorylation Oxidative Phosphorylation Pathology and Forensic Medicine Islets of Langerhans Adenosine Triphosphate Microscopy Electron Transmission Cell Line Tumor Insulin-Secreting Cells Insulin Secretion medicine Animals Homeostasis Secretion Inner mitochondrial membrane Molecular Biology Membrane Potential Mitochondrial Mice Knockout geography geography.geographical_feature_category ATP synthase biology Chemistry Insulin Proteins Cell Biology Islet Mitochondria Rats Cell biology Mice Inbred C57BL Glucose biology.protein Reactive Oxygen Species |
| Zdroj: | Laboratory Investigation. 102:69-79 |
| ISSN: | 0023-6837 |
| DOI: | 10.1038/s41374-021-00670-x |
| Popis: | Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1-/-) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1-/- mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1-/-, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1-/- β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink