Hypothesis

Nuclear acetyl-CoA generated at mitochondrial-associated membranes (MAMs) by ACSS2 preferentially fuels HAT complexes containing CBP, whereas ACLY-derived acetyl-CoA at the nucleoplasm fuels p300-containing complexes, creating a spatial code that determines tissue-specific histone acetylation patterns during aging.

Mechanistic Basis

Recent work shows that ACLY and ACSS2 are the main nuclear acetyl-CoA producers, yet their subcellular localization influences which HATs they support. We propose that ACSS2 is enriched at MAMs where it interacts with the mitochondrial citrate carrier and the scaffolding protein GRP75, positioning its product near CBP, which is recruited to MAMs through its interaction with the peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α). In contrast, ACLY remains diffuse in the nucleoplasm, allowing its acetyl-CoA to be accessed by p300, which binds chromatin through bromodomain interactions with acetylated histones H3K27ac. Aging reduces NAD+ levels, diminishing sirtuin activity and shifting the balance toward ACLY‑dependent p300 acetylation in metabolically active tissues such as liver, while neuronal tissues retain MAM integrity, preserving ACSS2‑CBP signaling and neuroprotective gene expression. This model explains why acetate supplementation rescues histone acetylation in brain but not liver, and why calorie restriction, which lowers cytosolic acetyl‑CoA, preferentially reduces p300 activity and extends lifespan.

Testable Predictions

1. Spatial mapping – Proximity ligation assays will detect ACSS2‑GRP75‑CBP triads at MAMs in young mouse hypothalamus and hippocampus, but these interactions will decline with age in liver hepatocytes.
2. Metabolic flux – Supplying ^13C‑acetate will label histone H3K9ac preferentially at promoters of TFEB targets in neurons, whereas ^13C‑glucose will label H3K27ac at metabolic gene promoters in liver; inhibition of ACLY with SB‑204990 will reduce the latter without affecting the former.
3. Functional outcome – Disrupting the MAM scaffold (e.g., GRP75 knock‑down) will decrease CBP‑mediated acetylation of the Foxo3 promoter in neurons, increase mitochondrial ROS, and accelerate age‑related memory decline, while overexpressing a mitochondria‑targeted ACLY construct will rescue p300 activity in liver and ameliorate age‑associated steatosis.
4. Physiological read‑out – Mice fed a high‑acetate diet will show improved glucose tolerance and reduced hypothalamic NF‑κB signaling only when GRP75 is intact; loss of GRP75 will abolish these benefits, confirming the requirement of MAM‑localized ACSS2‑CBP signaling for systemic metabolic health.

These predictions can be addressed with subcellular fractionation, click‑chemistry based acetyl‑CoA tracing, CRISPR‑mediated isoform tagging, and longitudinal behavioral and metabolic phenotyping. If the data support the model, targeting MAM‑associated ACSS2‑CBP signaling could serve as a tissue‑specific strategy to uncouple harmful acetylation from beneficial metabolic remodeling during aging.