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

Although the role of pancreatic beta-cell macroautophagy/autophagy is well known, that of beta-cell mitophagy is unclear. We investigated the changes of lysosomal Ca2+ by mitochondrial or metabolic stress that can modulate TFEB activation and, additionally, the role of TFEB-induced mitophagy in beta-cell function. Mitochondrial or metabolic stress induces mitophagy, which is mediated by lysosomal Ca2+ release, increased cytosolic [Ca2+] and subsequent TFEB activation. Lysosomal Ca2+ release is replenished by ER -> lysosome Ca2+ refilling through ER Ca2+ exit channels, which is important for the increase of cytosolic [Ca2+] and mitophagy by mitochondria stressors. High-fat diet (HFD) feeding augments pancreatic beta-cell mitophagy, probably as an adaptation to metabolic stress. HFD-induced increase of beta-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 Delta beta-cell mice, HFD-induced glucose intolerance and beta-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 Ca2+ release in conjunction with ER -> lysosome Ca2+ refilling is important for TFEB activation and mitophagy induction, which contributes to pancreatic beta-cell adaptation to metabolic stress.