ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2004
Excitotoxic calcium overload in a subpopulation of mitochondria triggers delayed death in hippocampal neurons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 146 citations in OpenAlex.
- Molecular mechanisms of microglia- and astrocyte-driven neurorestoration triggered by application of electromagnetic fields.Croatian medical journal · 2019Pooled it
- How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.Communications biology · 2026Review
- Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.bioRxiv : the preprint server for biology · 2026Article
- Mitochondrial CaBiomolecules · 2026Review
- Primary cortical neurons precipitate and extrude large mitochondria-associated calcium-phosphate sheets with a bone-precursor-like ultrastructure.Molecular brain · 2026Article
- Primary cortical neurons precipitate and extrude large mitochondria-associated calcium-phosphate sheets with a bone-precursor-like ultrastructure.bioRxiv : the preprint server for biology · 2025Article
- Mitochondrial CaCell calcium · 2025Article
- Physical Exercise Improves the Neuronal Function in Ischemic Stroke Via Microglial CBMolecular neurobiology · 2025Article
- Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy.Acta neuropathologica communications · 2024Article
- Mitochondrial calcium cycling in neuronal function and neurodegeneration.Frontiers in cell and developmental biology · 2023Review
- The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders.Translational neurodegeneration · 2022Review
- Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.Translational neurodegeneration · 2022Review
- Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington's Disease.Cells · 2021Article
- Building a Bridge Between NMDAR-Mediated Excitotoxicity and Mitochondrial Dysfunction in Chronic and Acute Diseases.Cellular and molecular neurobiology · 2021Review
- Review
- Monitoring mitochondrial translation in living cells.EMBO reports · 2021Article
- Mitochondrial Dynamics: A Potential Therapeutic Target for Ischemic Stroke.Frontiers in aging neuroscience · 2021Review
- Lipopolysaccharide FromFrontiers in molecular neuroscience · 2021Article
- The Role of Adenine Nucleotide Translocase in the Mitochondrial Permeability Transition.Cells · 2020Review
- Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
In neurons, excitotoxic stimulation induces mitochondrial calcium overload and the release of pro-apoptotic proteins, which triggers delayed cell death. The precise mechanisms of apoptogen release, however, remain controversial. To characterize the linkage between mitochondrial calcium load and cell vulnerability, and to test the hypothesis that only a subpopulation of mitochondria damaged by calcium overload releases apoptogens, we have measured directly the concentrations of total Ca (free plus bound) in individual mitochondria and monitored in parallel structural changes and the subcellular localization of pro-apoptotic cytochrome c after NMDA overstimulation in cultured hippocampal neurons. Beyond transient elevation of cytosolic calcium and perturbation of Na+/K+ homeostasis, NMDA stimulation induced dramatic, but mainly reversible, changes in mitochondria, including strong calcium elevation, membrane potential depolarization, and variable swelling. Elevation of matrix Ca in the approximately one-third of mitochondria that were strongly swollen, as well as the absence of swelling when Ca2+ entry was abolished, indicate an essential role for Ca overload. Shortly after NMDA exposure, cytochrome c, normally localized to mitochondria, became diffusely distributed in the cytoplasm, coincident with the appearance of severely swollen mitochondria with ruptured outer membranes; under these conditions, cytochrome c was retained in intact mitochondria, implying that it was released mainly from damaged mitochondria. Consistent with the role of mitochondrial Ca overload, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone decreased Ca accumulation, prevented cytochrome c release, and was neuroprotective. These results support a mechanism in which delayed excitotoxic death involves apoptogen release from a subpopulation of calcium-overloaded mitochondria, whereas other, undamaged mitochondria maintain normal function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.