Mitochondrial Ca²⁺ efflux controls neuronal metabolism and long-term memory across species

From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits. By knocking down the mitochondrial Ca²⁺ exporter Letm1, we favour Ca²⁺ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H⁺/Ca²⁺ exchange. The resulting increase in mitochondrial Ca²⁺ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.