Mitochondrial protein alterations in vascular dementia: evidence from Mendelian randomization, transcriptomics, and a chronic hypoperfusion model.
Overview
- Graduate School of Hunan University of Chinese Medicine, Changsha, Hunan, China
- Department of Neurology, Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, Hunan, China
- Institute of Innovation and Applied Research, Hunan University of Chinese Medicine, Changsha, Hunan, China
Abstract
Objective: Mitochondrial dysfunction is a key pathological feature of vascular dementia (VaD), yet the specific systemic and localized proteins involved remain unclear. We aim to utilize Mendelian randomization (MR) of plasma proteomics and Gene Expression Omnibus (GEO) datasets to identify systemic circulating biomarkers associated with VaD risk, and subsequently use in vivo models to investigate whether these systemic signals correspond to actual neuropathological mitochondrial changes in the brain.
Methods: We first identified candidate proteins associated with VaD risk through a two-sample MR analysis of plasma proteomics and GWAS data. Candidate genes were then assessed for differential expression using the GEO dataset GSE122063. Finally, the proteins were validated in a Bilateral Common Carotid Artery Occlusion (2-VO) rat model by evaluating pathological features and measuring its expression levels via Western Blot.
Results: Mendelian randomization analysis identified four proteins nominally linked to VaD: protective factors (AIFM1, COX5B) and risk factors (NDUFV2, NUDT5). However, cross-referencing these genetic predictions with GEO transcriptomics (GSE122063) and a 2-VO rat model revealed distinct tiers of evidentiary support. COX5B emerged as the most robust targets, demonstrating unidirectional consistency across all three analytical layers. NUDT5 showed partial consistency, supported by genetic and animal data, though its transcriptomic alteration fell short of the threshold. Conversely, AIFM1 and NDUFV2 displayed clear directional contradictions between the genetic/
Conclusion: Rather than universally validating all four genetic candidates, this rigorous multi-layer triangulation specifically pinpoints the dysregulation of COX5B as high-confidence, consistent drivers of mitochondrial impairment in VaD. Acknowledging the inconsistent complexities of AIFM1, NDUFV2, and NUDT5. Therapeutic strategies targeting the cleanly triangulated protein offer a more reliable, disease-modifying approach for VaD intervention.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE122063, at NCBI GEO; found in the text, “Bioinformatics exploration”
Data availability statement
The datasets presented in this study can be found in online repositories. The names of the repository/
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 10 authors, 6 keywords, 31 references.
Cite
This paper
Liu, Q., Tan, H., Tong, K., Luo, R., Li, H., Qiu, F., Wang, S., Xie, L., Zhang, X., & Wu, D. (2026). Mitochondrial protein alterations in vascular dementia: evidence from Mendelian randomization, transcriptomics, and a chronic hypoperfusion model. Frontiers in neurology, 17, 1794851. https://
BibTeX
@article{liu2026mitochon
author = {Liu, Qian and Tan, Huizhong and Tong, Keke and Luo, Ruhai and Li, Hanquan and Qiu, Feng and Wang, Shiliang and Xie, Le and Zhang, Xiuli and Wu, Dahua},
title = {{Mitochondrial protein alterations in vascular dementia: evidence from Mendelian randomization, transcriptomics, and a chronic hypoperfusion model}},
journal = {Frontiers in neurology},
year = {2026},
month = jul,
volume = {17},
pages = {1794851},
publisher = {Frontiers Media SA},
issn = {1664-2295},
doi = {10.3389/
url = {https://
pmid = {42494396},
pmcid = {PMC13391407}
}
RIS
TY - JOUR
AU - Liu, Qian
AU - Tan, Huizhong
AU - Tong, Keke
AU - Luo, Ruhai
AU - Li, Hanquan
AU - Qiu, Feng
AU - Wang, Shiliang
AU - Xie, Le
AU - Zhang, Xiuli
AU - Wu, Dahua
TI - Mitochondrial protein alterations in vascular dementia: evidence from Mendelian randomization, transcriptomics, and a chronic hypoperfusion model
T2 - Frontiers in neurology
J2 - Front Neurol
PY - 2026
DA - 2026/
VL - 17
SP - 1794851
SN - 1664-2295
PB - Frontiers Media SA
DO - 10.3389/
UR - https://
LA - en
ER -
CSL-JSON
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