@article {70288, title = {Mitochondrial Ca efflux controls neuronal metabolism and long-term memory across species.}, journal = {Nat Metab}, year = {2026}, month = {2026 Feb 11}, abstract = {

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 exporter Letm1, we favour Ca retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H/Ca exchange. The resulting increase in mitochondrial Ca 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.

}, issn = {2522-5812}, doi = {10.1038/s42255-026-01451-w}, url = {https://doi.org/10.1038/s42255-026-01451-w}, author = {Amrapali Vishwanath, Anjali and Comyn, Typhaine and Mira, Rodrigo G and Brossier, Claire and Pascual-Caro, Carlos and Faour, Maya and Boumendil, Kahina and Chintaluri, Chaitanya and Ramon-Duaso, Carla and Fan, Ruolin and Ghosh, Kishalay and Farrants, Helen and Berwick, Jean-Paul and Sivakumar, Riya and Lopez-Manzaneda, Mario and Schreiter, Eric R and Preat, Thomas and Vogels, Tim P and Rangaraju, Vidhya and Busquets-Garcia, Arnau and Placais, Pierre-Yves and Pavlowsky, Alice and de Juan-Sanz, Jaime} } @article {70083, title = {An expanded palette of bright and photostable organellar Ca2+ sensors}, journal = {eLife}, year = {2025}, month = {2025 Aug 26}, abstract = {

The use of fluorescent sensors for functional imaging has revolutionized the study of organellar Ca2+\ signaling. However, understanding the dynamic interplay between intracellular Ca2+\ sinks and sources has been hindered by the lack of bright, photostable, and multiplexed measurements in different organelles, limiting our ability to define how Ca2+\ shapes cell physiology across fields of biology. Here we introduce a new toolkit of chemigenetic organellar Ca2+\ indicators whose color is tunable by reconstituting their fluorescence with different exogenous rhodamine dye-ligands, which significantly expand the capacity for multiplexing organellar Ca2+\ measurements. These sensors, which we named ER-HaloCaMP and Mito-HaloCaMP, are optimized to report Ca2+dynamics in the endoplasmic reticulum (ER) and mitochondria of mammalian cells and neurons, and show significantly improved brightness, photostability and responsiveness when compared to current best-in-class alternatives. Using either red or far-red dye-ligands, both ER-HaloCaMP and Mito-HaloCaMP enable visualizing ER and mitochondrial Ca2+\ dynamics in neuronal axons, a subcellular location that only contains a few ER tubules and small mitochondria, structural limitations that have impaired measurements with previous red sensors. To show the expanded multiplexing capacities of our toolkit, we measured interorganellar Ca2+\ fluxes simultaneously in three different subcellular compartments in live cells, revealing that the amplitude of ER Ca2+release controls the efficacy of ER-mitochondria Ca2+\ coupling in a cooperative manner. Organellar HaloCaMPs enable also measuring Ca2+\ dynamics in intact brain tissue from flies and rodents, demonstrating their versatility across biological models. Our new toolkit provides an expanded palette of bright, photostable and responsive organellar Ca2+\ sensors, which will facilitate future studies of intracellular Ca2+\ signaling across fields of biology in health and disease.

}, doi = {10.7554/elife.107845.1}, url = {http://dx.doi.org/10.7554/eLife.107845.1}, author = {Moret, Agathe and Farrants, Helen and Fan, Ruolin and Zingg, Kelsey G and Silva, Bryon and Roselli, Camilla and Oertner, Thomas G and Gee, Christine E and Hadjieconomou, Dafni and Rangaraju, Vidhya and Schreiter, Eric R and de Juan-Sanz, Jaime} } @article {69756, title = {Periodic ER-plasma membrane junctions support long-range Ca signal integration in dendrites.}, journal = {Cell}, volume = {188}, year = {2025}, month = {01/2025}, pages = {484-500.e22}, abstract = {

Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at \~{}1\ μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca channels and ER Ca-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca homeostasis, and local activation of the Ca/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca release at ER-PM junctions over 20\ μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.

}, keywords = {Animals, Calcium, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Membrane, Dendrites, Endoplasmic Reticulum, Hippocampus, Humans, Male, Mice, Rats, Ryanodine Receptor Calcium Release Channel}, issn = {1097-4172}, doi = {10.1016/j.cell.2024.11.029}, author = {Benedetti, Lorena and Fan, Ruolin and Weigel, Aubrey V and Moore, Andrew S and Houlihan, Patrick R and Kittisopikul, Mark and Park, Grace and Petruncio, Alyson and Hubbard, Philip M and Pang, Song and Xu, C Shan and Hess, Harald F and Saalfeld, Stephan and Rangaraju, Vidhya and Clapham, David E and De Camilli, Pietro and Ryan, Timothy A and Lippincott-Schwartz, Jennifer} } @article {69704, title = {Periodic ER-plasma membrane junctions support long-range Ca signal integration in dendrites.}, journal = {Cell}, year = {2024}, month = {2024 Dec 18}, abstract = {

Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at \~{}1\ μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca channels and ER Ca-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca homeostasis, and local activation of the Ca/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca release at ER-PM junctions over 20\ μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2024.11.029}, author = {Benedetti, Lorena and Fan, Ruolin and Weigel, Aubrey V and Moore, Andrew S and Houlihan, Patrick R and Kittisopikul, Mark and Park, Grace and Petruncio, Alyson and Hubbard, Philip M and Pang, Song and Xu, C Shan and Hess, Harald F and Saalfeld, Stephan and Rangaraju, Vidhya and Clapham, David E and De Camilli, Pietro and Ryan, Timothy A and Lippincott-Schwartz, Jennifer} }