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

• Published in: Cell reports (Cambridge) Vol. 43; no. 2; p. 113681
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.02.2024; Elsevier
• Subjects: Alzheimer's disease; Animals; Biological Transport; Calcium; calcium overload; Cell Death; CP: Neuroscience; Drosophila; frontotemporal dementia; Huntington's disease; MCU; Mitochondria; mitochondrial calcium; NCLX; neurodegeneration; Neurodegenerative Diseases; Parkinson's disease; Parkinson's disease; NCLX; CP: Neuroscience; Drosophila; neurodegeneration; frontotemporal dementia; Huntington's disease; calcium overload; Alzheimer's disease; MCU; mitochondrial calcium
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113681

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. [Display omitted] •Drosophila models of multiple neurodegenerative diseases have increased neuronal MERCs•Disease model mitochondria have elevated basal Ca2+ and reduced Ca2+ buffering capacity•Reducing mCa2+ uptake via MCU loss rescues phenotypes across a broad range of disease models•Increasing mCa2+ efflux via NCLX overexpression is also beneficial across disease models Twyning et al. show using a single in vivo platform that reducing mitochondrial calcium uptake via MCU or increasing efflux via NCLX is beneficial across a variety of different disease models. These findings underscore the pathogenic role of mitochondrial calcium in neurodegeneration and highlight its potential as a therapeutic target.