| First Author | Park K | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 1300 |
| PubMed ID | 35288580 | Mgi Jnum | J:327283 |
| Mgi Id | MGI:7259446 | Doi | 10.1038/s41467-022-28874-9 |
| Citation | Park K, et al. (2022) Lysosomal Ca(2+)-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic beta-cells to metabolic stress. Nat Commun 13(1):1300 |
| abstractText | Although autophagy is critical for pancreatic beta-cell function, the role and mechanism of mitophagy in beta-cells are unclear. We studied the role of lysosomal Ca(2+) in TFEB activation by mitochondrial or metabolic stress and that of TFEB-mediated mitophagy in beta-cell function. Mitochondrial or metabolic stress induced mitophagy through lysosomal Ca(2+) release, increased cytosolic Ca(2+) and TFEB activation. Lysosomal Ca(2+) replenishment by ER- > lysosome Ca(2+) refilling was essential for mitophagy. beta-cell-specific Tfeb knockout (Tfeb(Deltabeta-cell)) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O2 consumption. Tfeb(Deltabeta-cell) mice showed aggravation of HFD-induced glucose intolerance and impaired insulin release. Metabolic or mitochondrial stress induced TFEB-dependent expression of mitophagy receptors including Ndp52 and Optn, contributing to the increased mitophagy. These results suggest crucial roles of lysosomal Ca(2+) release coupled with ER- > lysosome Ca(2+) refilling and TFEB activation in mitophagy and maintenance of pancreatic beta-cell function during metabolic stress. |
