Neuronal compartmentalization results in “impoverished” axonal mitochondria

Mitochondria differ depending on their location within a neuron. Morphological heterogeneity between somatic, dendritic, and axonal mitochondria is well established. Emerging evidence suggests that further specialization is needed to meet the unique demands of different neuronal compartments. However, the molecular and functional diversity of mitochondria within a neuron remains poorly understood. Here, we utilized proteomics in MitoTag mice to profile somatodendritic and axonal mitochondria across four distinct neuron types, thereby generating a compendium of intracellular mitochondrial diversity. Combining proteomics, functional, and immunofluorescence analyses, we demonstrated that axonal mitochondria are not defined by the presence of unique proteins, but rather by the selective loss or preservation of specific pathways compared to their somatodendritic counterparts. This results in “impoverished” axonal mitochondria, which are characterized by diminished mtDNA expression and impaired oxidative phosphorylation yet retain other pathways, such as fatty acid metabolism. Bioinformatic analyses of multiomic data identified local translation as one mechanism underlying compartment-specific diversity. Together, these findings provide a comprehensive in vivo framework for understanding mitochondrial specialization across neuronal compartments.