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Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.
Twyning, Madeleine J; Tufi, Roberta; Gleeson, Thomas P; Kolodziej, Kinga M; Campesan, Susanna; Terriente-Felix, Ana; Collins, Lewis; De Lazzari, Federica; Giorgini, Flaviano; Whitworth, Alexander J.
Afiliación
  • Twyning MJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
  • Tufi R; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
  • Gleeson TP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
  • Kolodziej KM; Department of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UK.
  • Campesan S; Department of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UK.
  • Terriente-Felix A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
  • Collins L; Department of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UK.
  • De Lazzari F; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
  • Giorgini F; Department of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UK.
  • Whitworth AJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: a.whitworth@mrc-mbu.cam.ac.uk.
Cell Rep ; 43(2): 113681, 2024 Feb 27.
Article en En | MEDLINE | ID: mdl-38236772
ABSTRACT
Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas Límite: Animals Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Neurodegenerativas Límite: Animals Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos