Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.

Overview

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^-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2. METHODS: Cortico-hippocampal tissue from Ndufs4^-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets. 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^-/- mice showing greater compensatory adaptations and treatment responses. 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.