Document Type
Article
Publication Date
8-1-2025
Original Citation
Gao H,
Jensen K,
Nesbitt J,
Ostroot M,
Cary G,
Wiley J,
Trushin S,
Watzlawik J,
Springer W,
Galkin A,
Baloni P,
Funk C,
Trushina E.
Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy. Alzheimers Dement. 2025;21(8):e70519.
Keywords
JMG, Animals, Alzheimer Disease, Electron Transport Complex I, Mice, Disease Models, Animal, Female, Humans, Male, Mice, Knockout, Mitochondrial Diseases, Mitochondria, Brain, Transcriptome
JAX Source
Alzheimers Dement. 2025;21(8):e70519.
ISSN
1552-5279
PMID
40731203
DOI
https://doi.org/10.1002/alz.70519
Grant
Consortia grant to Emory-Sage-SGC-JAX U54AG065187 (G.C. and J.W.)
Abstract
INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4
METHODS: Cortico-hippocampal tissue from Ndufs4
RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4
DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.
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