Molecular Tuning of the Axonal Mitochondrial Ca Uniporter Ensures Metabolic Flexibility of Neurotransmission

The brain is a vulnerable metabolic organ and must adapt to different fuel conditions to sustain function. Nerve terminals are a locus of this vulnerability, but how they regulate ATP synthesis as fuel conditions vary is unknown. We show that synapses can switch from glycolytic to oxidative metabolism, but to do so, they rely on activity-driven presynaptic mitochondrial Ca uptake to accelerate ATP production. We demonstrate that, whereas mitochondrial Ca uptake requires elevated extramitochondrial Ca in non-neuronal cells, axonal mitochondria readily take up Ca in response to small changes in external Ca. We identified the brain-specific protein MICU3 as a critical driver of this tuning of Ca sensitivity. Ablation of MICU3 renders axonal mitochondria similar to non-neuronal mitochondria, prevents acceleration of local ATP synthesis, and impairs presynaptic function under oxidative conditions. Thus, presynaptic mitochondria rely on MICU3 to facilitate mitochondrial Ca uptake during activity and achieve metabolic flexibility.