Glycogen: A must have storage to survive stressful emergencies

Abstract

Mechanisms of adaptation to acute changes in osmolarity are fundamental for life. When exposed to hyperosmotic stress, cells and organisms utilize conserved strategies to prevent water loss and maintain cellular integrity and viability. The production of glycerol is a common strategy utilized by the nematode Caenorhabditis elegans (C. elegans) and many other organisms to survive hyperosmotic stress. Specifically, the transcriptional upregulation of glycerol-3-phosphate dehydrogenase, a rate-limiting enzyme in the production of glycerol, has been previously implicated in many model organisms. However, what fuels this massive and rapid production of glycerol upon hyperosmotic stress has not been clearly elucidated. We have recently discovered an AMPK-dependent pathway that mediates hyperosmotic stress resistance in C. elegans. Specifically, we demonstrated that the chronic activation of AMPK leads to glycogen accumulation, which under hyperosmotic stress exposure, is rapidly degraded to mediate glycerol production. Importantly, we demonstrate that this strategy is utilized by flcn-1 mutant C. elegans nematodes in an AMPKdependent manner. FLCN-1 is the worm homolog of the human renal tumor suppressor Folliculin (FLCN) responsible for the Birt-Hogg-Dub e neoplastic syndrome. Here, we comment on the dual role for glycogen in stress resistance: it serves as an energy store and a fuel for osmolyte production. We further discuss the potential utilization of this mechanism by organisms in general and by human cancer cells in order to survive harsh environmental conditions and notably hyperosmotic stress.

Metabolite profiling of infection-associated metabolic markers of onchocerciasis

“…Interestingly, a hypothetical protein OVOC3987 has its best match to sn-3-glycerol-3-phosphate transporter (GlpT) in the PRK database. It needs to be ascertained whether glycerol-3-phosphate is taken up as an intermediate metabolite towards energy needs or towards osmotic stress [35]. Glycerol-3- phosphate is also produced by the breakdown of glycerophosphocholine to choline.…”

The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

“…AMPK is a heterotrimeric enzyme, which monitors the energy status and maintains energy homeostasis under metabolic stress by activating catabolic processes and inhibiting anabolic pathways [25-27]. We have previously shown that loss of FLCN or expression of a FLCN mutant unable to bind FNIP/AMPK led to chronic AMPK activation, resulting in increased ATP levels through an elevated glycolytic flux, oxidative phosphorylation and autophagy [28-30]. Importantly, we have shown that loss of FLCN mediates resistance to oxidative stress, heat, anoxia, obesity, and hyperosmotic stresses via AMPK activation in C. elegans and mammalian models [28-31].…”

Glucose as a Major Antioxidant: When, What for and Why It Fails?

“…It was noted that main life-and health-span promoting interventions such as caloric restriction, intermittent fasting and exercise have in common that the depletion of glycogen stores [44], thus reducing the protective capacity of glycogen and exposing the cells to moderate hormetic oxidative stress. Glycogen stores are not simply an intracellular source of glucose, they also have an important signaling function [54] and are protective against a number of stressful situations, namely hyper/hypo osmotic stress [55], anoxia/hypoxia [56] etc. In addition, growing evidence indicates that a metabolic switch from utilization of glucose, which is abundant in western diets, to ketone bodies use derived from fatty acids is an evolutionarily conserved trigger-point responsible for health effects from intermittent fasting, caloric restriction and exercise [57].…”