Hypothesis

Persistent mitochondrial 8‑oxoguanine (8-oxoG) does not merely reflect oxidative damage; it functions as a reversible epigenetic‑like mark that recruits the DNA glycosylase NEIL1 and the histone acetyltransferase p300 to mitochondrial DNA (mtDNA) and adjacent nuclear chromatin, thereby suppressing transcription of nuclear‑encoded mitochondrial genes (NEMGs). This recruitment reduces mitochondrial biogenesis, amplifies reactive oxygen species (ROS) production, and accelerates the decline of base excision repair (BER) enzymes, creating a feed‑forward loop that drives neuronal senescence and neurodegeneration.

Mechanistic rationale

1. 8-oxoG as a binding platform – Oxidized guanine can alter the local DNA helix, increasing affinity for NEIL1, which normally excises 8-oxoG but can also act as a scaffold when its catalytic activity is limited by low APE1/OGG1 levels.
2. NEIL1‑p300 complex – NEIL1 interacts with p300, transferring acetyl groups to nearby histones on nuclear chromatin that associates with mtDNA‑nucleoid complexes, leading to histone H3K27ac loss and a repressive chromatin state at promoters of NEMGs such as TFAM, NRF1, and COX5B.
3. Transcriptional silencing – Reduced NEMG expression lowers mitochondrial copy number and oxidative phosphorylation efficiency, raising mitochondrial ROS.
4. ROS‑BER decline – Elevated ROS further oxidizes guanine, overwhelming the already diminished OGG1/APE1 pool, increasing 8-oxoG levels and reinforcing the cycle.
5. Neuronal vulnerability – Post‑mitotic neurons rely heavily on short‑patch BER and lack robust backup repair; hippocampal neurons show baseline low BER capacity, making them early sites of this loop.

Testable predictions

• Prediction 1: In aged mouse hippocampi, chromatin immunoprecipitation (ChIP) for NEIL1 and p300 will show increased occupancy at 8-oxoG‑enriched mtDNA regions and at promoters of NEMGs.
• Prediction 2: Pharmacological inhibition of the NEIL1‑p300 interaction (e.g., using a small‑molecule disruptor) will restore NEMG mRNA levels, increase mitochondrial respiration, and reduce cortical 8-oxoG accumulation without altering OGG1/APE1 expression.
• Prediction 3: Neuronal overexpression of a catalytically dead NEIL1 mutant that retains p300 binding will exacerbate transcriptional silencing and accelerate cognitive decline in APP/PS1 mice, whereas a NEIL1 mutant unable to bind p300 will be protective.
• Prediction 4: In human induced pluripotent stem cell‑derived neurons from AD donors, CRISPR‑based base editing to convert 8-oxoG to guanine at specific NEMG promoters will rescue transcriptional activity and ameliorate ROS‑induced apoptosis.

Falsifiability

If ChIP assays reveal no enrichment of NEIL1 or p300 at 8-oxoG sites, or if disrupting their interaction fails to improve mitochondrial gene expression or ROS levels despite confirmed 8-oxoG presence, the hypothesis would be refuted. Likewise, if NEMG transcription remains unchanged after precise 8-oxoG removal, the epigenetic‑like role of the lesion is unsupported.

Broader impact

Establishing 8-oxoG as a regulatory signal links DNA repair dynamics directly to epigenetic control of mitochondrial function, offering a dual‑target strategy: enhance BER capacity while blocking maladaptive NEIL1‑p300 signaling to break the vicious cycle in aging and Alzheimer’s disease.

References

[1] https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13905 [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC5576886/ [3] https://pmc.ncbi.nlm.nih.gov/articles/PMC10247526/ [4] https://www.alzdiscovery.org/uploads/cognitive_vitality_media/OGG1_Agonists.pdf [5] https://pmc.ncbi.nlm.nih.gov/articles/PMC3834072/ [6] https://pure.johnshopkins.edu/en/publications/dna-base-excision-repair-activities-in-mouse-models-of-alzheimers-3/