Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol

Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, England, UK.
The Journal of Cell Biology (Impact Factor: 9.69). 10/2005; 170(7):1101-11. DOI: 10.1083/jcb.200504035
Source: PubMed

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.

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Available from: Sovan Sarkar, Aug 26, 2015
    • "A primordial signaling pathway regulating autophagy, which is conserved from yeast to humans, is mediated by the mammalian target of rapamycin complex 1 (mTORC1), which inhibits autophagy by phosphorylating proteins such as ATG1 and ATG13 that act upstream in phagophore formation (Hosokawa et al., 2009; Jung et al., 2009). However, several mTORC1-independent pathways have been described, including low inositol triphosphate levels (Sarkar et al., 2005), which activate autophagy by activating AMP-activated protein kinase (AMPK). Low inositol triphosphate levels reduce "
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    Journal of Experimental Medicine 06/2015; 212(7). DOI:10.1084/jem.20150956 · 13.91 Impact Factor
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    • "Lithium, carbamazepine and sodium valproate are currently approved drugs used to treat mood disorders and epilepsy. They target d-myo-inositol-1,4,5-triphosphate (IP3)-regulated pathway, depleting intracellular inositol, and therefore induce autophagy (Sarkar et al. 2005; Rubinsztein et al. 2007). Tamoxifen is a drug currently used to treat a wide variety of diseases, from breast cancer to mood disorders and infertility, among others. "
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    • "We have previously shown that novel mTOR-independent pathways exist to activate autophagy (Sarkar et al, 2005; Williams et al, 2008). Through high-throughput screening of a library of 214 compounds enriched for drugs already FDA-approved for non-infectious indications (see Methods), we identified several compounds able to activate mTOR-independent autophagic killing of intracellular mycobacteria (after 24-h treatment). "
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