Mitochondria-Centered Metabolic Microdomains: Regulatory Roles in Synaptic Plasticity and Circuit Homeostasis

The metabolism of neuronal activity is highly localized and cannot be sustained by cell-wide distribution of energy. Neurons and glia organize metabolic enzymes, mitochondria, lipid droplets, and endoplasmic reticulum (ER) contacts into spatially localized microdomains that dynamically couple energy generation to synaptic activity. These metabolic microdomains engage with calcium signaling, redox, and kinase pathways to regulate synaptic plasticity, intrinsic excitability, and homeostatic scaling. Dysregulation of this spatial metabolic control increasingly appears to contribute to neurodevelopmental disorders, epilepsy, and neurodegeneration. Because mitochondrial positioning, dynamics, and ER-mitochondria contacts occupy a central and recurring position among these microdomains, this review focuses in particular on mitochondria-associated metabolic mechanisms while integrating glycolytic, lipid, and astrocytic compartments into a unified framework. We propose that metabolic compartmentalization may constitute an underappreciated modulatory layer influencing circuit function, though the extent and mechanistic specificity of this regulation remain to be fully established. In this review, we discuss current innovations in imaging, metabolomics, and organelle biology to suggest a model whereby metabolic compartmentalization may serve as a modulatory tier of circuit stability and adaptability.