Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity

The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.