Hypothesis

Age‑dependent decline of mitochondrial OGG1 leads to persistent 8‑oxoguanine (8-oxoG) in mtDNA, which elevates mitochondrial ROS and triggers a retrograde calcium signal that inhibits the CaMK‑CREB pathway in the nucleus. Reduced CREB phosphorylation diminishes APE1 transcription, weakening nuclear BER and allowing nuclear 8-oxoG to accumulate. Persistent nuclear 8-oxoG serves as an epigenetic lesion that recruits HDAC‑containing complexes to the promoters of OGG1 and APE1, further suppressing their expression. This creates a self‑reinforcing loop that accelerates BER failure, synaptic loss, and cognitive aging.

Mechanistic Rationale

• Mitochondrial OGG1 loss is documented in aging neurons and correlates with bioenergetic decline [OGG1 mitochondrial decline].
• Elevated mtROS from unrepaired 8-oxoG can activate mitochondrial calcium uniporter, increasing cytosolic Ca2+ that overwhelms CaMKII signaling [CaMK‑CREB regulation of APE1].
• CREB phosphorylation directly drives APE1 transcription; its reduction lowers APE1 protein levels [APE1 expression and CREB]; APE1 loss accelerates cognitive decline [APE1 knockout effects].
• Nuclear 8-oxoG can act as an epigenetic mark, attracting HDAC1/2 complexes that deacetylate histone BER gene promoters, a mechanism observed for other oxidative lesions [8-oxoG epigenetic role].
• HDAC‑mediated repression of OGG1 and APE1 would further diminish repair capacity, closing the loop.

Testable Predictions

1. In aged neurons, mitochondrial 8-oxoG levels will be inversely correlated with nuclear p‑CREB and APE1 expression.
2. Pharmacological scavenging of mitochondrial ROS (e.g., MitoTEMPO) will restore CaMK‑CREB signaling and increase APE1 without altering OGG1 expression.
3. Overexpression of a mitochondrially targeted OGG1 (mito‑OGG1) will reduce mtROS, normalize Ca2+ flux, rescue p‑CREB, and increase APE1 levels, even in old animals.
4. Chromatin immunoprecipitation will show increased HDAC1/2 binding at OGG1 and APE1 promoters in aged neurons, which diminishes after mito‑OGG1 rescue or HDAC inhibition.
5. Disrupting the retrograde Ca2+ signal (e.g., with MCU inhibitor Ru360) will break the loop, lowering nuclear 8-oxoG and improving cognitive performance in aged mice.

Experimental Approaches

• Measurements: Quantify mt8-oxoG (LC‑MS/MS), cytosolic Ca2+ (GCaMP imaging), p‑CREB (Western blot), APE1/OGG1 levels (immunofluorescence), and HDAC promoter occupancy (ChIP‑qPCR) in hippocampal neurons from young (3 mo) vs aged (24 mo) mice.
• Interventions: AAV‑delivery of mito‑OGG1, MitoTEMPO treatment, Ru360 infusion, or HDACi (SAHA) administration; assess synaptic markers (PSD‑95, synaptophysin) and behavior (Morris water maze).
• Human relevance: Post‑mortem human hippocampal tissue – compare mt8-oxoG, p‑CREB, APE1, and HDAC binding across Braak stages.

If the loop exists, rescuing mitochondrial OGG1 or blocking the retrograde Ca2+ signal should simultaneously restore nuclear CREB activity, elevate APE1, reduce nuclear 8-oxoG, and ameliorate age‑related cognitive decline. Failure to observe these changes would falsify the hypothesis.