Mitochondrial-nuclear crosstalk: A central axis in Alzheimer’s disease
Year: 2026
Type: review
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and survival pathways, making it a critical determinant of brain aging and AD vulnerability. Despite its importance, the mechanisms coordinating this bidirectional dialogue and how their breakdown drives neurodegeneration remain poorly understood. This review highlights the major molecular pathways governing mito-nuclear signaling under physiological conditions, including anterograde pathways (PGC-1α/NRF1/2/TFAM) and retrograde stress responses (ROS, calcium, mitokines, and the mitochondrial unfolded protein response). In AD, these pathways are disrupted, leading to mitochondrial dysfunction, impaired proteostasis, metabolic reprogramming, and inflammation. Emerging evidence suggests that mito‑nuclear signaling deficits arise early often preceding classical Aβ and tau pathology positioning them as potential upstream drivers of disease. We further discuss therapeutic strategies aimed at restoring mito‑nuclear communication, including NAD⁺ supplementation, mitophagy enhancers, mitochondria‑targeted antioxidants, and gene‑based approaches, emphasizing the importance of combinatorial and cell‑type‑specific interventions. Finally, we highlight how single‑cell and spatial transcriptomic technologies are enabling high‑resolution mapping of mito‑nuclear dynamics in aging and AD. Together, these insights underscore mito‑nuclear signaling as a promising but underexplored therapeutic target for modifying AD progression.
Source: Ageing Research Reviews
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,520
Awards: Impact of mitochondrial structure on cellular homeostasis and hepatic injury, Compartment-specific mitochondrial unfolded protein response in Alzheimer’s disease, Mitochondrial calcium uptake in Alzheimer’s disease, G4445903950, Mitochondrial calcium heterogeneity in cerebrovascular system during Alzheimer's disease, G6319566628
OpenAlex ID: W7155648564