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Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
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Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
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Journal Article
Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
2022
Overview
Although autophagy is critical for pancreatic β-cell function, the role and mechanism of mitophagy in β-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 β-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. β-cell-specific
Tfeb
knockout (
Tfeb
Δβ-cell
) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome
c
oxidase a
c
tivity or O
2
consumption.
Tfeb
Δβ-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 β-cell function during metabolic stress.
Autophagy is important for pancreatic β-cell function, however, the role of mitophagy and mechanism for mitophagy in β-cells are unclear. Here the authors report that in stressed β-cells, lysosomal Ca
2+
release promotes mitophagy via activation of the transcription factor EB (TFEB) and loss of β-cell TFEB aggravates glucose intolerance during high-fat diet.
