LETM1 knockdown prolongs mitochondrial calcium and boosts long-term memory in flies and mice
Researchers report that reducing LETM1 slows mitochondrial calcium efflux about threefold, over-activates neuronal mitochondrial metabolism in memory circuits, and enhances long-term olfactory memory in both Drosophila and mice.
- LETM1 acts as a mitochondrial H+/Ca2+ exporter in neurons and its EF-hand calcium binding domain is required for export function.
- Knocking down LETM1 slowed mitochondrial calcium efflux roughly threefold in axons and caused about a 70% reduction in dendritic mitochondrial efflux.
- Prolonged mitochondrial calcium retention over-activates mitochondrial metabolism and produces presynaptic ATP accumulation under physiological activity.
- The metabolic increase depends on Ca2+-activated PDP1 and is activity dependent, and it is prevented by PDP1 knockdown or by blocking neuronal firing with TTX.
- LETM1 knockdown targeted to central memory circuits produced robust long-term olfactory memory in flies and mice in training conditions where wild-type animals failed to remember.
- Manipulating LETM1 did not substantially alter cytosolic calcium dynamics, mitochondrial or cytosolic pH, or basic synaptic vesicle cycling, indicating a specific effect on mitochondrial calcium handling.
- The results reveal an evolutionarily conserved mechanism linking mitochondrial calcium efflux timing to neuronal metabolic state and long-term memory formation.