Lithium induces autophagy by inhibiting inositol monophosphatase

TLDR

Macroautophagy clears aggregate‑prone cytosolic proteins, and the only pharmacologic enhancer known is rapamycin, which inhibits mTOR. The study aims to identify a novel mTOR‑independent pathway that regulates autophagy. Lithium induces autophagy by inhibiting inositol monophosphatase, depleting free inositol and lowering IP3, thereby enhancing clearance of mutant huntingtin and α‑synucleins independently of GSK3β and mTOR, suggesting therapeutic potential for neurodegenerative diseases.

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 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.