Age-dependent oxidation and deamidation of synaptic mitochondrial proteins (including VDAC1, CypD/PPID, and MICOS complex members) impairs calcium handling and ATP generation, creating a chronic energy deficit that uncouples synaptic vesicle release probability from activity demands and triggers compensatory synaptic loss.
Curated pathway from expert analysis
flowchart TD
A["Aging-Induced Protein Oxidation<br/>Synaptic Mitochondrial Proteome"]
B["CypD PPID Cyclophilin D Deamidation<br/>mPTP Opening Threshold Lowered"]
C["VDAC1 Oxidation<br/>Electron Transport Chain Disruption"]
D["MICOS Complex Member Dysfunction<br/>Cristae Remodeling Impaired"]
E["Mitochondrial Calcium Handling Impaired<br/>Synaptic Ca2+ Dysregulation"]
F["ATP Generation Decreases<br/>Energy-Demand Mismatch at Synapses"]
G["Vesicle Release Probability Drops<br/>Synaptic Transmission Failure"]
H["Synaptic Atrophy<br/>AD Neurodegeneration"]
A --> B
A --> C
A --> D
B --> E
C --> F
D --> E
E --> F
F --> G
G --> H
style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for PPID yet. Search RCSB →
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 PPID (Cyclophilin D).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF oxidative damage to VDAC1, CypD/PPID, and MICOS complex proteins is prevented specifically at synaptic mitochondria via targeted mitochondrial antioxidant delivery (MitoQ or MitoTempo, 100nM) in ag | Targeted mitochondrial antioxidant treatment in aged flies will prevent oxidation of mitochondrial proteins, restore calcium handling (measured via mitochondria | — no observation — | pending | 0.65 |
| IF PPID/CypD is genetically knocked out or pharmacologically inhibited in aged neurons (18-24 months in mice), THEN synaptic vesicle release probability will remain coupled to activity demands during | Inhibition of PPID/CypD in aged neurons will restore the linear relationship between stimulation frequency and release probability (measured via optical vesicle | — no observation — | pending | 0.72 |