Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models
Summary: 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 mi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724000093 |
| _version_ | 1797291781355732992 |
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| author | Madeleine J. Twyning Roberta Tufi Thomas P. Gleeson Kinga M. Kolodziej Susanna Campesan Ana Terriente-Felix Lewis Collins Federica De Lazzari Flaviano Giorgini Alexander J. Whitworth |
| author_facet | Madeleine J. Twyning Roberta Tufi Thomas P. Gleeson Kinga M. Kolodziej Susanna Campesan Ana Terriente-Felix Lewis Collins Federica De Lazzari Flaviano Giorgini Alexander J. Whitworth |
| author_sort | Madeleine J. Twyning |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-07T19:42:40Z |
| format | Article |
| id | doaj.art-9603e362758f41768755e35b7a1109b6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-07T19:42:40Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9603e362758f41768755e35b7a1109b62024-02-29T05:18:34ZengElsevierCell Reports2211-12472024-02-01432113681Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease modelsMadeleine J. Twyning0Roberta Tufi1Thomas P. Gleeson2Kinga M. Kolodziej3Susanna Campesan4Ana Terriente-Felix5Lewis Collins6Federica De Lazzari7Flaviano Giorgini8Alexander J. Whitworth9MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UKDepartment of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UKDepartment of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UKDepartment of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UKDepartment of Genetics and Genome Biology, University of Leicester, University Road, Leicester LE1 7RH, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724000093CP: Neuroscience |
| spellingShingle | Madeleine J. Twyning Roberta Tufi Thomas P. Gleeson Kinga M. Kolodziej Susanna Campesan Ana Terriente-Felix Lewis Collins Federica De Lazzari Flaviano Giorgini Alexander J. Whitworth Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models Cell Reports CP: Neuroscience |
| title | Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models |
| title_full | Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models |
| title_fullStr | Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models |
| title_full_unstemmed | Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models |
| title_short | Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models |
| title_sort | partial loss of mcu mitigates pathology in vivo across a diverse range of neurodegenerative disease models |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724000093 |
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