Mitochondrial 8‑oxoG–Driven Retrograde Suppression of Nuclear Base Excision Repair in Aging Neurons

Hypothesis

Age‑dependent loss of mitochondrial OGG1‑1b permits 8‑oxoG accumulation in mtDNA, which triggers a retrograde signaling cascade that directly suppresses nuclear BER enzymes (OGG1, APE1, Polβ) through NAD+ depletion and cGAS‑STING activation.

Mechanistic Model

1. mtDNA damage – Reduced OGG1‑1b activity lets 8‑oxoG persist in mitochondrial genomes [https://pmc.ncbi.nlm.nih.gov/articles/PMC10247526/].
2. Retrograde signal – Oxidized mtDNA is released into the cytosol, where it is sensed by cGAS, producing STING‑dependent type‑I IFN signaling.
3. IFN‑mediated transcriptional repression – IRF1, downstream of STING, binds promoters of nuclear BER genes (OGG1, APE1, Polβ) and reduces their expression, a mechanism observed in interferon‑treated neurons.
4. Metabolic amplification – Chronic STING activation consumes NAD+ via PARP1, lowering the NAD+/NADH ratio and further inhibiting SIRT1‑dependent deacetylation of APE1, decreasing its activity [https://www.aginganddisease.org/EN/10.14336/AD.2022.0331].
5. Vicious loop – Declining nuclear BER raises nuclear 8‑oxoG, which augments mitochondrial ROS production, reinforcing mtDNA damage.

Predictions & Tests

• Prediction 1: In aged neurons, cytosolic mtDNA fragments and phospho‑STING levels will correlate inversely with nuclear OGG1, APE1, and Polβ protein amounts.
  • Test: Isolate cytosol from young vs. aged mouse hippocampus, quantify mtDNA by qPCR and STING phosphorylation by Western blot; correlate with nuclear BER enzyme levels.
• Prediction 2: Pharmacological inhibition of cGAS or STING will rescue nuclear BER activity and reduce nuclear 8‑oxoG even without altering mitochondrial OGG1‑1b.
  • Test: Treat aged rat neuronal cultures with cGAS inhibitor (RU.521) or STING antagonist (C‑176); measure OGG1/APE1/Polβ activity and nuclear 8‑oxoG via comet assay with FPG.
• Prediction 3: NAD+ supplementation will partially restore APE1 activity in aged neurons despite persistent mtDNA 8‑oxoG.
  • Test: Provide aged neurons with NR (nicotinamide riboside); assay APE1 incision activity and NAD+ levels.
• Prediction 4: Neuron‑specific OGG1‑1b overexpression will lower cytosolic mtDNA release, diminish STING signaling, and thereby increase nuclear BER enzyme expression.
  • Test: Use AAV‑Syn‑OGG1‑1b in aged mice; assess cytosolic mtDNA, p‑STING, IFN‑β mRNA, and nuclear BER protein levels.

Falsifiability

If any of the following observations hold, the hypothesis is refuted:

• mtDNA 8‑oxoG accumulation does not increase cytosolic mtDNA or STING activation in aged neurons.
• Inhibiting cGAS/STING fails to elevate nuclear BER enzyme activity or lower nuclear 8‑oxoG.
• NAD+ repletion does not improve APE1 activity despite normalized NAD+ pools.
• OGG1‑1b overexpression reduces mitochondrial 8‑oxoG but leaves cytosolic mtDNA, STING signaling, and nuclear BER unchanged.

Implications

This model positions mitochondrial DNA damage as an upstream driver of nuclear repair decline, explaining why BER deficits appear in human AD brains but not in many murine models that lack robust mtDNA‑induced interferon responses. It suggests combinatorial strategies—boosting mitochondrial OGG1, blocking cGAS‑STING, and replenishing NAD+—may be required to break the cycle and restore genomic integrity in aging neurons.