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

## TL;DR

Increasing mitochondrial calcium retention in neurons improves long-term memory in both flies and mice.

## Contribution

A conserved mechanism linking mitochondrial calcium retention to enhanced memory formation across species is identified.

## Key findings

- Knocking down Letm1 increases mitochondrial Ca2+ retention in neurons.
- Enhanced mitochondrial metabolism improves long-term memory in flies and mice.
- The mechanism is evolutionarily conserved across species.

## Abstract

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.

Boosting mitochondrial metabolism in neurons in central memory circuits by enhancing Ca2+ retention in the mitochondrial matrix is shown to improve long-term memory formation in flies and mice.