Repository logo

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

Published version

Repository DOI



Change log


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


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.



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


Volume Title



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