Declining SIRT3 activity leaves SOD2, IDH2, and permeability-transition regulators hyperacetylated, reducing mitochondrial antioxidant capacity, NADPH support, and resistance to pore opening. Increased ROS and energetic failure can then further suppress NAD+-dependent SIRT3 function, forming a secondary resilience-collapse loop. This is biologically coherent but currently the least direct and least well-validated self-amplifying mechanism.
Curated pathway from expert analysis
flowchart TD
A["NAD+ in Mitochondria<br/>Metabolic State Signal"]
B["SIRT3 Activation<br/>Mitochondrial Deacetylase"]
C["IDH2 Deacetylation<br/>TCA Cycle Enhanced"]
D["SOD2 Deacetylation<br/>K68/K122 Activation"]
E["Complex I/III Deacetylation<br/>OXPHOS Efficiency"]
F["ROS Reduction<br/>Oxidative Stress Attenuated"]
G["SIRT3 Reduced in Aging/AD<br/>Mitochondrial Hyperacetylation"]
H["Mitochondrial Dysfunction<br/>Bioenergetic Failure"]
A --> B
B --> C
B --> D
B --> E
C --> F
D --> F
E --> F
G -.->|"reduces"| B
G --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#81c784,color:#81c784
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for SIRT3; yet. Search RCSB →
Median TPM across 13 brain regions for SIRT3; SOD2; IDH2; PPIF from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for SIRT3; SOD2; IDH2; PPIF.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF NAD+ levels are experimentally reduced by 50% using FK866 (NAMPT inhibitor) in Sirt3+/+ neurons, THEN SIRT3 activity will decrease (>40% reduction in deacetylation of SOD2), mitochondrial ROS will | NAD+ depletion will synergize with SIRT3 loss to produce accelerated mitochondrial dysfunction, confirming the self-amplifying resilience-collapse loop; combine | — no observation — | pending | 0.35 |
| IF SIRT3 is genetically deleted in primary neurons (Sirt3 knockout or CRISPR knockout in iPSC-derived neurons), THEN hyperacetylation of SOD2 (Lys122), IDH2 (Lys83), and PPIF (Lys148) will increase wi | Hyperacetylation of SIRT3 target proteins will precede and correlate with functional deficits in antioxidant capacity and mitochondrial permeability resistance, | — no observation — | pending | 0.45 |