Enhancing Mitochondrial Function Improves Memory in Flies and Mice
The brain requires a great deal of energy to function. That energy is provided by mitochondria, hundreds of these organelles in every cell producing the chemical energy store molecule adenosine triphosphate (ATP), that activity reliant on the nutrients and oxygen delivered via the vascular system. The brain operates at the limit of its metabolic capacity even in youth, as demonstrated by the fact that exercise and the consequent increased supply of blood to the brain transiently increases cognitive function. Mitochondrial function declines with age, and this has consequences. But as researchers show here, improving the capacity of mitochondria to provide the cell with energy can enhance cognitive function at any age.
Expensive energy usage in neurons must be limited to avoid unnecessary overconsumption of fuels in the brain that could otherwise be useful for survival. During neuronal activity, synapses synthesize the exact levels of energy that are consumed during each firing event, without underproducing or overproducing ATP. While the work of several laboratories has identified how mitochondrial metabolism is upregulated on demand in activated neurons to preserve the metabolic integrity of synapses, the importance and the molecular identity of mechanisms slowing down mitochondrial metabolism after firing have remained elusive.
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.