Summary: Forming a long-term memory is an energy-intensive process that requires neurons to produce a massive amount of fuel (ATP). A new study has discovered a way to “overclock” this energy production to significantly boost memory.
By inhibiting a protein called LETM1, which exports calcium from mitochondria, researchers were able to keep calcium inside the mitochondria longer. This prolonged the production of ATP without reaching toxic levels. In both fruit flies and mice, this “metabolic boost” allowed the animals to form lasting memories after just a single training session—a task that usually requires multiple repetitions.
Key Facts
- The Energy-Memory Link: Long-term memory consolidation requires sustained energy investment. Increasing ATP production in neurons directly enhances this process.
- LETM1 Protein: This protein regulates the exit of calcium from mitochondria. Reducing its expression keeps calcium in the “powerhouse” longer, accelerating energy production.
- Single-Session Success: Fruit flies and mice with boosted mitochondrial energy formed long-term memories (lasting over 24 hours) after only one exposure to a stimulus, bypassing the need for repetitive training.
- Specific to Long-Term Memory: The metabolic boost did not affect middle-term memory, suggesting the energy is specifically utilized for the “expensive” task of permanent consolidation.
- Conservation Across Species: Because LETM1 is present in all eukaryotic organisms, this mechanism of memory optimization is likely fundamental and shared by humans.
Source: Paris Brain Institute
The brain is one of the most energy-demanding organs in the body. Whenever we articulate a thought, reason, or form a new memory, neurons become active. This activity requires fuel in the form of ATP, a molecule produced by mitochondria—the cell’s powerhouses.
When a neuron is stimulated, intracellular calcium levels rise; part of this calcium enters the mitochondria, where it accelerates the Krebs cycle, a cascade of chemical reactions that boosts ATP production.
“The entry and exit of calcium within mitochondria allow energy production to be finely tuned to the demands of brain activity,” says Jaime de Juan-Sanz, head of the PreSyn team at the Paris Brain Institute.
“Until now, however, this mechanism had mainly been studied in situations that cause an energy deficit impairing information transmission at synapses.”
Working with colleagues from the Brain Plasticity Laboratory at ESPCI in Paris, the Hospital del Mar Research Institute in Barcelona, the Institute of Science and Technology in Vienna and the Max Planck Florida Institute for Neuroscience in Jupiter, the researchers asked a different question: what happens if we leverage mitochondrial calcium to increase energy production in neurons beyond what the brain needs to function normally?
Retaining Mitochondrial Calcium
To answer this question, the team focused on LETM1, a protein located in the inner mitochondrial membrane that helps export calcium from the mitochondrial matrix. By reducing its expression in cellular models, the researchers slowed calcium extrusion following neuronal activation.
As a result, calcium remains longer inside the mitochondria, prolonging metabolic stimulation and leading to overproduction of ATP.
“What makes this approach particularly interesting is that it extends a physiological cellular signal without overloading mitochondria with calcium, which could otherwise become toxic to neurons,” explains Jaime de Juan-Sanz.
The team then examined the impact of this controlled metabolic boost in living animals. In both species studied, fruit flies and mice, LETM1 inhibition had a significant impact on behavior, particularly performance in tasks requiring long-term memory.
Memories That Last Longer
Normally, if a fruit fly experiences an odor paired with a mild punishment only once, it remembers the association for a few hours, but not the next day. To establish a lasting memory, the experiment must be repeated several times.
However, researchers found that when LETM1 expression is reduced in mushroom body neurons (the center of olfactory memory in arthropods), a single training session is sufficient to produce a memory that persists for more than 24 hours.
“By contrast, we did not observe the same effect on middle-term memory. It appears that our manipulation does not enhance all forms of memory indiscriminately, but specifically those that require sustained energy investment,” the researcher adds.
The same type of Pavlovian conditioning was conducted in mice, with comparable results. This mechanism of memory consolidation appears to be conserved across very different species—especially given that the LETM1 protein is present in all eukaryotic organisms.
What If the Brain Could Work Better?
These findings suggest that slightly increasing the energy available to neurons can improve certain aspects of long-term memory performance.
“Perhaps this phenomenon is not limited to memory and could also be used to stimulate other neural circuits—to improve cognitive endurance, for example,” argues Jaime de Juan-Sanz.
We are still far from being able to modulate the brain’s energy resources on demand. The genetic strategy used in this study is complex, and LETM1 dysregulation is implicated in several human diseases, including Wolf-Hirschhorn syndrome.
Nevertheless, the study invites a rethinking of energy’s role in brain function: it is not merely fuel, like a flashlight battery, but a genuine regulator of the intensity and duration of neuronal processes—more akin to a control panel.
“Most importantly, we have demonstrated that the brain may possess an unexpected capacity for optimization. That was far from obvious! The next step is to develop tools capable of modulating mitochondrial calcium with greater precision—for example, through optogenetics—to determine how far we can enhance memory consolidation,” concludes the researcher.
Key Questions Answered:
A: Not yet. This study used genetic manipulation to inhibit the LETM1 protein. While it proves the brain has an “untapped capacity for optimization,” we are still a long way from a pill or treatment that can modulate mitochondrial energy on demand without side effects.
A: Consolidation is expensive! Your brain is like a flashlight; it has to decide which memories are worth the “battery power.” Normally, it only invests in memories that are reinforced multiple times. This study shows that if you provide “extra batteries,” the brain can save memories much more easily.
A: That is the hope. If we can find safe ways to boost neuronal energy, we might be able to help people whose brains struggle to consolidate new information due to energy deficits or mitochondrial decay.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this memory research news
Author: Marie Simon
Source: Paris Brain Institute
Contact: Marie Simon – Paris Brain Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species” by Anjali Amrapali Vishwanath, Typhaine Comyn, Rodrigo G. Mira, Claire Brossier, Carlos Pascual-Caro, Maya Faour, Kahina Boumendil, Chaitanya Chintaluri, Carla Ramon-Duaso, Ruolin Fan, Kishalay Ghosh, Helen Farrants, Jean-Paul Berwick, Riya Sivakumar, Mario Lopez-Manzaneda, Eric R. Schreiter, Thomas Preat, Tim P. Vogels, Vidhya Rangaraju, Arnau Busquets-Garcia, Pierre-Yves Plaçais, Alice Pavlowsky & Jaime de Juan-Sanz. Nature Metabolism
DOI:10.1038/s42255-026-01451-w
Abstract
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.
