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

Mitochondrial calcium (Ca ²⁺ ) uptake augments metabolic processes and buffers cytosolic Ca ²⁺ levels; however, excessive mitochondrial Ca ²⁺ can cause cell death. Disrupted mitochondrial function and Ca ²⁺ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca ²⁺ 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 Ca ²⁺ levels, as well as reduced mitochondrial Ca ²⁺ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca ²⁺ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca ²⁺ 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.
Competing Interests: Declaration of interests T.P.G. is now an employee of Costello Medical Consulting, Ltd.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)