ATP Synthase Abundance in Neuronal Extracellular Vesicles Reflects Changes in the Mitochondria of Parent Neurons

Mitochondrial proteins are found in extracellular vesicles (EVs) such as neuron-derived EVs (NEVs). Yet whether and how NEV-borne mitochondrial proteins relate to the state of mitochondria in the parent neurons is unclear. Studying the mitochondrial ATP synthase in primary hippocampal neurons and their released EVs, we discovered that the abundance of ATP synthase in NEVs echoes the catalytic activity level of ATP synthase in neurons. We also observed, unexpectedly, that within the neuron, the quantity of ATP synthase remains constant irrespective of the level of its activity. Using non-canonical amino acid tagging coupled with proximity ligation assay, we found that the amount of nascent ATP synthase is linearly correlated to its activity, which may contribute to maintaining the overall quantity of ATP synthase in the neuron stable. Furthermore, we identified a sub-population of mitochondria-derived vesicles (MDVs) that carry ATP synthase and are not targeted to lysosomal degradation. Our findings suggest a strategy used by neurons in regulating and fine-tuning mitochondrial ATP synthase through MDV and NEV generation. Further studies are needed to elucidate the relationship between ATP synthase-containing-NEVs and -MDVs.