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 Ca<sup>2+</sup> exporter Letm1, we favour Ca<sup>2+</sup> retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H<sup>+</sup>/Ca<sup>2+</sup> exchange. The resulting increase in mitochondrial Ca<sup>2+</sup> 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.
Authors
- Rodrigo G. Mira (ORCID: https://orcid.org/0009-0009-8508-244X)
- Alice Pavlowsky (ORCID: https://orcid.org/0000-0001-6873-0577)
- Ruolin Fan (ORCID: https://orcid.org/0000-0002-6405-5196)
- Helen Farrants (ORCID: https://orcid.org/0000-0003-2494-886X)
- Anjali Amrapali Vishwanath (ORCID: https://orcid.org/0000-0002-9888-0928)
- Vidhya Rangaraju (ORCID: https://orcid.org/0000-0002-6716-4312)
- Carlos Pascual-Caro (ORCID: https://orcid.org/0000-0002-2345-393X)
- Mario López-Manzaneda (ORCID: https://orcid.org/0000-0002-1366-4143)
- Thomas Préat (ORCID: https://orcid.org/0000-0001-9976-1763)
- Typhaine Comyn (ORCID: https://orcid.org/0000-0002-3834-4373)
- Pierre-Yves Plaçais (ORCID: https://orcid.org/0000-0001-8426-4465)
- Jean-Paul Berwick
- Riya Sivakumar
- Carla Ramon-Duaso
- Jaime de Juan-Sanz
- Tim P. Vogels
- Arnau Busquets-Garcia
- Kishalay Ghosh
- Kahina Boumendil
- Claire Brossier
- Eric R. Schreiter
- Maya Faour
Institutions
- Centre National de la Recherche Scientifique (FR)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- Institute of Science and Technology Austria (AT)
- Janelia Research Campus (US)
- Université Paris Sciences et Lettres (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut de Myologie (FR)
- Max Planck Florida Institute for Neuroscience (US)
- Pitié-Salpêtrière Hospital (FR)
- Hospital Del Mar (ES)
- Laboratoire Plasticité du Cerveau (FR)
- Institut du Cerveau (FR)
- Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR)
- ESPCI Paris (FR)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-02-11
- DOI
- https://doi.org/10.1038/s42255-026-01451-w
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Silicon Valley Community Foundation
- Wellcome Trust
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Generalitat de Catalunya
- Fondation pour la Recherche Médicale
- École Supérieure de Physique et de Chimie Industrielles de la Ville de Paris
- Ministerio de Economía y Competitividad
- Max-Planck-Gesellschaft
- Centre National de la Recherche Scientifique
- National Institutes of Health