Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress

Abstract

Although the role of pancreatic -cell macroautophagy/autophagy is well known, that of -cell mitophagy is unclear. We investigated the changes of lysosomal Ca 2+ by mitochondrial or metabolic stress that can modulate TFEB activation and, additionally, the role of TFEB-induced mitophagy in cell function. Mitochondrial or metabolic stress induces mitophagy, which is mediated by lysosomal Ca 2+ release, increased cytosolic [Ca 2+ ] and subsequent TFEB activation. Lysosomal Ca 2+ release is replenished by ERlysosome Ca 2+ refilling through ER Ca 2+ exit channels, which is important for the increase of cytosolic [Ca 2+ ] and mitophagy by mitochondria stressors. High-fat diet (HFD) feeding augments pancreatic -cell mitophagy, probably as an adaptation to metabolic stress. HFD-induced increase of-cell mitophagy is reduced by tfeb KO, leading to increased ROS and decreased mitochondrial complex activity or oxygen consumption in tfeb-KO islets. In tfeb -cell mice, HFD-induced glucose intolerance and -cell dysfunction are aggravated. Expression of mitophagy receptor genes including Optn or Calcoco2 is increased by mitochondrial or metabolic stressors in a TFEB-dependent manner, likely contributing to increased mitophagy. These results suggest that lysosomal Ca 2+ release in conjunction with ERlysosome Ca 2+ refilling is important for TFEB activation and mitophagy induction, which contributes to pancreatic -cell adaptation to metabolic stress.

Topics & Concepts