Molecular Tuning of the Axonal Mitochondrial Ca<sup>2+</sup> Uniporter Ensures Metabolic Flexibility of Neurotransmission.

Overview

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, whereas mitochondrial Ca²⁺ uptake requires elevated extramitochondrial Ca²⁺ in non-neuronal cells, axonal mitochondria readily take up Ca²⁺ in response to small changes in external 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.