Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease.

Overview

1. Department of Health and Exercise Science Colorado State University Fort Collins Colorado USA
2. Columbine Health Systems Center for Healthy Aging Colorado State University Fort Collins Colorado USA

Abstract

Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double‐stranded RNA (mt‐dsRNA) as a potential trigger of inflammation. We examined mt‐dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt‐dsRNA signatures increased after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt‐dsRNA‐driven inflammation. In AD brains, mt‐dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin‐dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt‐dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age‐ and AD‐related neurodegeneration and identify mt‐dsRNA as a potential driver of chronic inflammation in the brain.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data Availability Statement

The datasets analyzed in this study are publicly available as described under the Data and Code Availability section.

Reproduced under the paper's license (CC BY), from the paper cited above.

Data and Code Availability

All RNA‐seq datasets used in this study are publicly available. The main datasets used here for analyses are ribo‐depleted RNA‐seq data from human prefrontal cortex and include: the NABEC dataset (105 neurologically normal individuals aged 19–86 years; see Table S1; Synapse ID: syn3270007) and ROSMAP dataset (218 individuals aged > 73 years with clinical diagnoses of no cognitive impairment [NCI], mild cognitive impairment [MCI], or AD [sporadic or genetic]; see Table S2; Synapse ID: syn3219045). Supporting RNA‐seq datasets include: PKR immunoprecipitated RNA in HeLa cells (GSE108986) (Kim, Park, et al. 2018), directly reprogrammed/induced human neurons (E‐MTAB‐3037) (Kim, Zheng, et al. 2018), DRP1 in human neuronal co‐culture (GSE237013) (Liaudanskaya et al. 2023), human muscle biopsy following in vivo Urolithin A treatment (GSE197273) (Singh et al. 2022), and BAX/BAK knock‐out in human lung fibroblasts (GSE196610) (Victorelli et al. 2023). Processed data tables and normalized mt‐dsRNA editing values are available from the corresponding author upon request, and analysis scripts can be found on GitHub at: racheldoser/Mitochondrial‐dsRNA‐RNAseq‐analyses (Doser 2026).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 6 keywords, 9 MeSH terms, 1 funder, 61 references.

Cite

This paper

Doser, R. L., & LaRocca, T. J. (2026). Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease. Aging cell, 25(7), e70616. https://doi.org/10.1111/acel.70616

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