Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic ß-cells to metabolic stress.
Nat Commun
; 13(1): 1300, 2022 03 14.
Article
em En
| MEDLINE
| ID: mdl-35288580
ABSTRACT
Although autophagy is critical for pancreatic ß-cell function, the role and mechanism of mitophagy in ß-cells are unclear. We studied the role of lysosomal Ca2+ in TFEB activation by mitochondrial or metabolic stress and that of TFEB-mediated mitophagy in ß-cell function. Mitochondrial or metabolic stress induced mitophagy through lysosomal Ca2+ release, increased cytosolic Ca2+ and TFEB activation. Lysosomal Ca2+ replenishment by ER- > lysosome Ca2+ refilling was essential for mitophagy. ß-cell-specific Tfeb knockout (TfebΔß-cell) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O2 consumption. TfebΔß-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 Ca2+ release coupled with ER- > lysosome Ca2+ refilling and TFEB activation in mitophagy and maintenance of pancreatic ß-cell function during metabolic stress.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mitofagia
/
Lisossomos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article