Calvo-Rodriguez, MariaHou, Steven S.Snyder, Austin C.Kharitonova, Elizabeth K.Russ, Alyssa N.Das, SudeshnaFan, ZhanyunMuzikansky, AlonaGarcia-Alloza, MonicaSerrano-Pozo, AlbertoHudry, EloiseBacskai, Brian J.2022-04-262022-04-262020-05-01Calvo-Rodriguez M, Hou SS, Snyder AC, Kharitonova EK, Russ AN, Das S, et al. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease. Nat Commun. 2020 May 1;11(1):2146.http://hdl.handle.net/10668/3567Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca2+ overload, but the effects of Aβ on mitochondrial Ca2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Naturally secreted soluble Aβ applied onto the healthy brain increases Ca2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca2+ transporter genes, but upregulation in the genes related to mitochondrial Ca2+ efflux pathways, suggesting a counteracting effect to avoid Ca2+ overload. We propose lowering neuronal mitochondrial Ca2+ by inhibiting the mitochondrial Ca2+ uniporter as a novel potential therapeutic target against AD.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/MitochondriaCalciumCell deathAmyloidBrainGenesMicroscopyAlzheimer diseaseLeadMitocondriasCalcioMuerte celularAmiloideEncéfaloMicroscopíaEnfermedad de AlzheimerPlomoMedical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer DiseaseMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Molecular Probe Techniques::Blotting, WesternMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Chemicals and Drugs::Inorganic Chemicals::Elements::Metals, Alkaline Earth::CalciumMedical Subject Headings::Anatomy::Cells::Cells, CulturedMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::CytosolMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immunologic Techniques::ImmunohistochemistryMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Membrane Potentials::Membrane Potential, MitochondrialMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BLMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::MitochondriaMedical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative DiseasesMedical Subject Headings::Anatomy::Nervous System::Neuronsresearch article32358564Acceso abierto10.1038/s41467-020-16074-22041-1723PMC7195480