Molecular tuning of the axonal mitochondrial Ca2+ uniporter ensures metabolic flexability 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 Ca2+ uptake to accelerate ATP production. We demonstrate that while in non-neuronal cells mitochondrial Ca2+ uptake requires elevated extramitochondrial Ca2+, axonal mitochondria readily take up Ca2+ in response to small changes in Ca2+. We identified the brain-specific protein MICU3 as a critical driver of this tuning of Ca2+ 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 Ca2+ uptake during activity and achieve metabolic flexibility.\n\nO_LISynapses rely on activity-driven mitochondrial ATP synthesis with oxidative fuels\nC_LIO_LIMitochondrial Ca2+ uptake is required to stimulate ATP synthesis in axons\nC_LIO_LIThe mitochondria Ca2+ uptake threshold is lower in axons than in non-neuronal cells\nC_LIO_LIMICU3 controls the Ca2+ sensitivity of MCU in axonal mitochondria\nC_LI