Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism
Year: 2025
Type: preprint
Abstract: Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo . Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Translational medicine and mechanistic studies of brain neurophysiology in Fragile X Syndrome, G4205231063, TEM for UT Southwestern Electron Microscopy Core Facility, G477572607, G5528378378, G5578310997, G5903603098, G6256846791, Catalytic Mechanism, Regulation and Drug-Target Potential of Bacterial Alarmone Hydrolases, Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model, Mechanistic Connection between Interorganellar Communication and Obesity-associated Diseases
OpenAlex ID: W4417520735