한빛사 논문
Kihyoun Park1,2, Myung-Shik Lee1,3,*
1Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
2Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University School of Medicine, Seoul, Korea.
3Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, Korea.
*Corresponding author.
Abstract
Although the role of pancreatic β-cell macroautophagy/autophagy is well known, that of β-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 β-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 β-cell mitophagy, probably as an adaptation to metabolic stress. HFD-induced increase ofβ-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 Δβ-cell mice, HFD-induced glucose intolerance and β-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 β-cell adaptation to metabolic stress.
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