Lithium induces autophagy by inhibiting inositol monophosphatase

Sovan Sarkar, R Andres Floto, Zdenek Berger, Sara Imarisio, Axelle Cordenier, Matthieu Pasco, Lynnette J Cook, David C Rubinsztein

Research output: Contribution to journalArticlepeer-review

733 Citations (Scopus)

Abstract

Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and alpha-synucleins. This effect is not mediated by glycogen synthase kinase 3beta inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.

Original languageEnglish
Pages (from-to)1101-11
Number of pages11
JournalJournal of Cell Biology
Volume170
Issue number7
DOIs
Publication statusPublished - 26 Sep 2005

Keywords

  • Animals
  • Autophagy
  • COS Cells
  • Cell Line, Tumor
  • Cercopithecus aethiops
  • Enzyme Inhibitors
  • Humans
  • Inositol
  • Lithium
  • Mutation
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Phosphoric Monoester Hydrolases
  • Protein Kinases
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • alpha-Synuclein

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