Memory loss is reversed by 'activating' the mitochondria in the brain

A French and Canadian team used a molecular switch to boost energy production from mitochondria inside brain cells, restoring memory in mice with dementia-like symptoms.

The work links energy failure in neurons to cognitive problems and points to a new target for therapy, as shown in a recent study.

The brain burns through fuel quickly, and trouble starts when its cellular power plants fall behind. Lead investigator Giovanni Marsicano from the University of Bordeaux (UB), supervised the research alongside collaborators in Bordeaux and Moncton.

Mitochondria linked to energy

Inside each neuron, mitochondria convert nutrients and oxygen into ATP, the cell’s spendable energy.

That reaction, called oxidative phosphorylation, keeps electrical signals firing and helps keep memory circuits stable, and it is already a focus of clinical strategies.

Researchers also see energy shortfalls early in diseases like Alzheimer’s, well before many neurons die.

A large human report showed widespread cellular stress and mitochondrial dysfunction across the Alzheimer’s brain, consistent with early bioenergetic failure.

Until now, it was hard to tell if failing mitochondria cause memory loss or simply show up as collateral damage. The new work attacks that question directly by turning the organelle up, then watching behavior change.

New switch for cellular power

The team built on chemogenetic tools called DREADDs that let scientists turn engineered receptors on with a lab-made drug and leave everything else alone, a method well known in neuroscience.

They redesigned a stimulatory receptor so it sits on mitochondria, then named it mitoDREADD-Gs.

When activated, this receptor triggers G proteins inside the organelle to kickstart energy production. The design lets researchers press a precise biochemical button without changing thousands of other cellular parts.

Turning on mitoDREADD-Gs rapidly raised mitochondrial membrane potential and oxygen consumption in brain tissue.

Mechanistically, the switch boosted intramitochondrial cAMP and PKA, a pathway known to tune respiration from within the organelle, as shown by classic cell biology work.

Results of the study

The group first tested a known form of amnesia triggered by tetrahydrocannabinol, the active compound in cannabis.

That impairment relies on cannabinoid receptors located on mitochondria in the memory center, the hippocampus.

With mitoDREADD-Gs turned on in hippocampal neurons, the THC-induced recognition memory deficit (RMD) disappeared.

The animals explored the new object again, a simple behavioral readout tied to long-term memory consolidation.

The team then moved to disease models. Mice that model frontotemporal dementia or Alzheimer’s disease, both showing early hippocampal bioenergetic defects, recovered recognition memory when their mitochondrial activity was temporarily boosted. 

“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases, suggesting that impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration,” explained Marsicano

Human memory and mitochondria

The hippocampus is a hub for forming and stabilizing long-term memories. It depends on a steady ATP supply to maintain synaptic strength during the hours after learning, when fragile traces become durable.

Energy deficits hit this process hard. If oxidative phosphorylation slows, neurotransmission weakens, plasticity fades, and cells compensate poorly, especially in aging or disease.

The new tool increased assembly and activity of complex I in the respiratory chain, a bottleneck for electron entry that shapes ATP output.

That local, reversible boost was enough to normalize behavior in two distinct dementia models, a strong sign that bioenergetics sit upstream of the memory symptoms.

What it does not prove yet

These experiments were done in mice and used viral delivery of engineered receptors alongside a designer drug. That is not a therapy for people, and safety would need rigorous study.

Short bursts of extra respiration helped, but constant stimulation may carry risk. Excess energy flux can increase reactive oxygen species, strain quality control, and stress vulnerable neurons.

The findings therefore map a mechanism and a target, not a ready-to-use treatment. Any clinical translation would need careful dosing windows, specific brain regions, and long-term monitoring.

Neurons, mitochondria, and memory

Many current approaches try to coax cells to make more mitochondria, ship healthy mitochondria into damaged tissue, or scavenge oxidative byproducts.

Reviews highlight growing tests of such strategies in animals and early trials in several diseases.

This study offers a different angle, a way to tune the existing power plants quickly and locally inside neurons.

By working with endogenous signaling, it avoids permanent genomic edits and keeps the intervention reversible.

Future work will probe how long the memory rescue can last, which cell types drive the effect, and whether similar bioenergetic tuning could help other cognitive domains beyond recognition memory.

If the answers continue to line up, mitochondria could shift from bystanders to central targets in the fight against dementia.

The study is published in Nature Neuroscience.

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