Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models

Madeleine J. Twyning, Roberta Tufi, Thomas P. Gleeson, Kinga M. Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander Whitworth

Research output: Contribution to JournalArticlepeer-review

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.
Original languageEnglish
Article number113681
Number of pages17
JournalCell Reports
Volume43
Issue number2
DOIs
Publication statusPublished - 17 Jan 2024

Keywords

  • Neurodegeneration
  • Parkinson's disease
  • Huntington's disease
  • Alzheimer's disease
  • Frontotemporal dementia
  • Mitochondrial calcium
  • MCU (Mitochondrial Calcium Uniporter)
  • NCLX (Sodium/Calcium/Lithium Exchanger)
  • Drosophila
  • Calcium overload

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