NECAB2 orchestrates an endosomal pathway of mitochondrial quality control at striatal synapses

Abstract

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control. We found that the neuronal calcium-binding protein NECAB2 ensures synaptic function in the striatum by increasing mitochondrial efficiency. NECAB2 associates with early endosomes and mitochondria at striatal synapses. Loss of NECAB2 dysregulates proteins of the endosomal ESCRT machinery and oxidative phosphorylation. Mitochondria from NECAB2-deficient mice are more abundant but less efficient. These mitochondria exhibit increased respiration and superoxide production but produce less ATP. This accumulation of faulty mitochondria is caused by a defective assembly of mitochondria with early endosomes in response to oxidative stress. Impairment of this mechanism causes loss of striatal synapses and behavioral dysfunctions such as reduced motivation and altered sensory gating. NECAB2 therefore orchestrates an endosomal pathway of mitochondrial quality control important for striatal function.