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

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. [ABSTRACT FROM AUTHOR]