Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress

Kihyoun Park, Hyejin Lim, Jinyoung Kim, Yeseong Hwang, Yu Seol Lee, Soo Han Bae, Hyeongseok Kim, Hail Kim, Shin Wook Kang, Joo Young Kim, Myung Shik Lee

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7 Citations (Scopus)


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 Ca2+ 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 Ca2+ release, increased cytosolic Ca2+ and TFEB activation. Lysosomal Ca2+ replenishment by ER- > lysosome Ca2+ refilling was essential for mitophagy. β-cell-specific Tfeb knockout (TfebΔβ-cell) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O2 consumption. TfebΔβ-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 β-cell function during metabolic stress.

Original languageEnglish
Article number1300
JournalNature communications
Issue number1
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
The authors thank Cha S-G and Park K-S for provision of probes for organelle Ca measurement, and Jae-Ho Cheong for Seahorse respirometry. ΔCnA-H151Q mutant and mRFP-LC3 were gifts from Scorrano L and Yoshimori T, respectively. GCaMP3-ML1 plasmid and ML-SI3 were provided by Xu H. INS-1 cells were from Wollheim C. Nfe2l2-KO mice were obtained from Yamamoto M. Flag-BirA(N-G78) and BirA(G79-C)-HA backbone vectors were from Rhee H-W. This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A2C3002924) and by the Bio&Medical Technology Development Program (2017M3A9G7073521). M.-S.L. is the recipient of a grant from the Faculty Research Assistance Program of Yonsei University College of Medicine (6-2016-0055) and A3 Foresight Program of the NRF (2015K2A2A6002060). 2+

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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