Mitochondrial calcium uniporter regulates odor learning and memory by controlling neuropeptide release

Despite growing understanding of the various roles mitochondria play in neurons, how they contribute to higher brain functions such as learning and memory remains underexplored. Here, using the nematode Caenorhabditis elegans, we found that the mitochondrial calcium uniporter (MCU) pore forming unit MCU-1 is required for aversive learning to specific odors sensed by a single sensory neuron, AWCON. MCU-1 expression was required in the sensory neuron at the time of odor conditioning for proper behavioral response to 60 min of prolonged odor exposure. Through genetic and pharmacological manipulation, we show evidence that MCU is activated in response to prolonged odor conditioning, causing mtROS production, leading to NLP-1 secretion. Finally, we show that the timing of MCU activation and neuropeptide release correspond with the OFF-neuron properties of the AWC neuron, suggesting that mitochondrial calcium entry and neuropeptide secretion coincide with AWC activation upon odor removal. Overall, our results demonstrate that, by regulating mitochondrial calcium influx, mitochondria can modulate the synaptic response to incoming stimuli in the sensory neuron, resulting in learning and modified behavior.