Lithium induces autophagy by inhibiting inositol monophosphatase

By Sovan Sarkar, R. A. Floto, Z. Berger, S. Imarisio, A. Cordenier, Matthieu Y. Pasco, L. Cook, D. Rubinsztein. Journal of Cell Biology, 2005

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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 α-synucleins. This effect is not mediated by glycogen synthase kinase 3β 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.

Subfields: Epidemiology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/52c31a786d413a8aacece8add5acd6e76cad5c91

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Citations in the corpus

Autophagy, amyloidogenesis and Alzheimer disease (2007, background): “presence of aggregates of mutant huntingtin, the pathogenic protein in Huntington disease (Ravikumar et al., 2002; Sarkar et al., 2005; Yamamoto et al., 2005; Shibata et al., 2006).”
Potential therapeutic applications of autophagy (2007, background): “This can be achieved with drugs such as lithium, carbamezapine and sodium valproate, which all act on inositol metabolism and results in decreased IP 3 (Ref”
Molecular mechanisms and potential therapeutical targets in Huntington's disease. (2010, background): “Sarkar and colleagues (500, 501) showed that combining inhibition of mTOR and inositol monophosphatase (IMPase) by rapamycin and lithium, respectively, resulted in additive clearance of mutant huntingtin in vitro, providing a basis for preclinical trials in HD models.”
Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. (2009, background): “We do not think that this is the only regulatory mechanism of autophagy because it has also been reported that there is an mTORindependent pathway for autophagy induction (Sarkar et al., 2005), and the effect of starvation is larger than rapamycin treatment (Supplemental Figure S3).”
Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. (2007, methodology): “Although these SMIRs and SMERs were discovered as modulators of the effects of rapamycin on yeast growth, we tested if they were also modulators of mammalian autophagy.”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, background): “MTORindependent regulation can be achieved through lithium, sodium valproate and carbamazepine, compounds that lower the myoinositol-1,4,5-triphosphate levels.(765) In vivo treatment of embryos with cadmium results in an increase in autophagy, probably to counter the stress, allowing cell survival t”
The roles of intracellular protein-degradation pathways in neurodegeneration (2006, background): “Recently, we found that autophagy can be regulated in an mTOR-independent manner by drugs that reduce intracellular inositol levels, such as lithium, valproate and carbamazepin”
Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. (2010, positive): “Constitutive InsP3R Ca 2+ Release Is Required to Inhibit Prosurvival Autophagy in Normal Conditions The InsP3R has been implicated in mTOR-independent autophagy (Criollo et al., 2007; Sarkar et al., 2005; Vicencio et al., 2009; Williams et al., 2008).”
Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium (2007, neutral): “Inhibition of IP3R by a pharmacological inhibitor (Xestospogin B), siRNA depletion or lithiummediated inhibition of IP3 synthesis triggers autophagosome formation, suggesting that IP3R activity inhibits autophagy.(22,48) This appears contradictory to data showing that ATP that induces IP3 synthesis ”
Rapamycin alleviates toxicity of different aggregate-prone proteins. (2006, background): “Also, new components of the TOR signalling network may provide new targets for autophagy induction (45,46) and there may be suitable mTOR-independent autophagy enhancers that may have similar beneficial effects (47).”