Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB

Diego L. Medina, Simone Di Paola, Ivana Peluso, Andrea Armani, Diego De Stefani, Rossella Venditti, Sandro Montefusco, Anna Scotto-Rosato, Carolina Prezioso, Alison Forrester, Carmine Settembre, Wuyang Wang, Qiong Gao, Haoxing Xu, Marco Sandri, Rosario Rizzuto, Maria Antonietta De Matteis, Andrea Ballabio

Research output: Contribution to journalArticlepeer-review


The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca 2+ signalling mechanism controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca 2+ release through mucolipin 1 (MCOLN1) activates calcineurin, which binds and dephosphorylates TFEB, thus promoting its nuclear translocation. Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect. Induction of autophagy and lysosomal biogenesis through TFEB required MCOLN1-mediated calcineurin activation. These data link lysosomal calcium signalling to both calcineurin regulation and autophagy induction and identify the lysosome as a hub for the signalling pathways that regulate cellular homeostasis.

Original languageEnglish
Pages (from-to)288-299
Number of pages12
Journalnature cell biology
Issue number3
Publication statusPublished - 2 Mar 2015
Externally publishedYes


Dive into the research topics of 'Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB'. Together they form a unique fingerprint.

Cite this