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 language | English |
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Article number | 113681 |
Number of pages | 17 |
Journal | Cell Reports |
Volume | 43 |
Issue number | 2 |
DOIs | |
Publication status | Published - 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