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

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.

Keywords: Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration.