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

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Twyning, Madeleine J 
Tufi, Roberta 
Gleeson, Thomas P 
Kolodziej, Kinga M 
Campesan, Susanna 

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.

Description

Keywords

Alzheimer's disease, CP: Neuroscience, Drosophila, Huntington's disease, MCU, NCLX, Parkinson's disease, calcium overload, frontotemporal dementia, mitochondrial calcium, neurodegeneration, Animals, Neurodegenerative Diseases, Mitochondria, Biological Transport, Calcium, Cell Death, Drosophila

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

43

Publisher

Elsevier BV
Sponsorship
European Research Council (309742)
Medical Research Council (MC_UU_00015/6)
Medical Research Council (MC_UU_00015/7)