Glycolytic enzymes localize to synapses under energy stress to support synaptic function

Abstract

SUMMARYChanges in neuronal activity create local and transient changes in energy demands at synapses. Here we discover a metabolic compartment that forms in vivo near synapses to meet local energy demands and support synaptic function in Caenorhabditis elegans neurons. Under conditions of energy stress, glycolytic enzymes redistribute from a diffuse localization in the cytoplasm to a punctate localization adjacent to synapses. Glycolytic enzymes colocalize, suggesting the ad hoc formation of a glycolysis compartment, or a 'glycolytic metabolon', that can maintain local levels of ATP. Local formation of the glycolytic metabolon is dependent on presynaptic scaffolding proteins, and disruption of the glycolytic metabolon blocks the synaptic vesicle cycle, impairs synaptic recovery, and affects locomotion. Our studies indicate that under energy stress conditions, energy demands in C. elegans synapses are met locally through the assembly of a glycolytic metabolon to sustain synaptic function and behavior. †

Synaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth

“…Isolating neurons by FACS allowed the authors to conclude that the induction of glycolytic genes was produced in neurons. Despite strong evidence indicating that glucose metabolism is activated by synaptic activity in neurons, these results do not oppose the ANLS, but supports the notion that neurons take up and metabolize through glycolysis in certain conditions (Zala et al, 2013;Lundgaard et al, 2015;Jang et al, 2016;Ashrafi et al, 2017;Díaz-García et al, 2017). Cell division, migration, and neurite growth require extraordinary levels of energy that would explain why the supply of energy in neurons is not limited to the astrocytic lactate during pre-and postnatal stages.…”

RNA promotes phase separation of glycolysis enzymes into yeast G bodies in hypoxia

“…Thus, G bodies and glycosomes may represent a case of convergent evolution. Similar structures also form in the neurons of C. elegans, where enzyme clustering in response to hypoxia was associated with proper synaptic function, suggesting that glycolysis enzymes coalesce to increase glycolysis and meet the local high energy demand during synapses (Jang et al, 2016). Furthermore, cancer cell lines form small aggregates of glycolysis enzymes even in the presence of oxygen, suggesting that concentrating glycolysis enzymes is a highly conserved process (Kohnhorst et al, 2017).…”

“…G bodies represent an addition to the known metabolic pathways organized by phase separation mechanisms. Three recent studies have demonstrated glycolysis enzyme coalescence in hypoxia, which is associated with increased rates of glucose flux (Jang et al, 2016;Jin et al, 2017;Miura et al, 2013). Thus, G bodies and glycosomes may represent a case of convergent evolution.…”

“…Recently, we and others demonstrated that glycolysis enzymes coalesce into membraneless cytoplasmic granules called glycolytic bodies (G bodies) in hypoxic stress in yeast, C. elegans, and mammalian cells (Jang et al, 2016;Jin et al, 2017;Miura et al, 2013).…”

“…In C. elegans, hypoxia rapidly induces the formation of foci containing glycolysis enzymes near presynaptic release sites in neurons. A phosphofructokinase mutant incapable of punctate localization disrupts synaptic vesicle clustering in neurons, suggesting that coalescence of glycolysis enzymes promotes synaptic function (Jang et al, 2016). However, the mechanism of G body formation remains poorly understood.…”