Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular life. When exposed to hyperosmotic stress, cells and organisms utilize conserved strategies to prevent water loss and maintain cellular integrity and viability. Here we identify a novel AMPK-dependent pathway of resistance to hypertonic stress mediated by the AMPK regulator flcn-1 in C. elegans. FLCN-1 is the worm homologue of the tumor suppressor Folliculin (FLCN), responsible for the Birt-Hogg-Dubé hereditary cancer disorder. We show that loss of flcn-1 increases glycogen stores in an AMPK dependent manner and that the glycogen reserves are rapidly degraded upon hypertonic stress, leading to a remarkable accumulation of the organic osmolyte glycerol, promoting resistance to hyperosmotic stress. Importantly, loss of AMPK, glycogen synthase or glycogen phospharylase, which are critical enzymes in glycogen metabolism, strongly suppressed the increased osmotic stress resistance in flcn mutant animals. We further demonstrate that glycerol 3-phosphate dehydrogenase-1 is strongly induced in flcn-1 animals upon hyperosmotic stress and that simultaneous loss of gpdh-1 and gpdh-2 abolished the flcn-1/AMPK-mediated osmotic stress phenotype. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in kidneys and renal tumors from a BHD patient. Since BHD is a renal hyperproliferation disorder, a mechanism of osmotic stress resistance in kidney hyperosmotic environments might explain tumorigenesis in BHD patients. Overall, our data indicate that FLCN is an evolutionary conserved regulator of glycogen metabolism, that might be acting as a tumor suppressor via AMPK-dependent accumulation of glycogen and organic osmolytes, resulting in an advantageous increase in proliferation and survival in hyperosmotic environments. .
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