Electron leak at complex I and destabilized inner-membrane architecture generate superoxide and lipid oxidation that damage ETC components, dissipate membrane potential, and further increase electron leak. This creates a direct mitochondrial self-amplifying loop, but it competes with alternative ROS origins such as iron chemistry, dopamine oxidation, and inflammatory oxidases. It is mechanistically plausible yet less complete as a whole-tissue explanation.
Curated pathway from expert analysis
flowchart TD
A["Complex I Core Subunits<br/>NDUFV1/NDUFV2 and mtDNA Partners"]
B["Cardiolipin-Dependent ETC Assembly<br/>Inner Membrane Stability"]
C["Electron Leak and ROS<br/>Local Oxidative Burst"]
D["Cardiolipin Peroxidation<br/>Cristae Injury"]
E["Mitochondrial Damage Loop<br/>Respiratory Failure Amplified"]
F["Neuron Bioenergetic Collapse<br/>Organelle-Centered Degeneration"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NDUFV1; yet. Search RCSB →
Median TPM across 13 brain regions for NDUFV1; NDUFV2; MT-ND genes; cardiolipin-associated ETC complexes 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 NDUFV1; NDUFV2; MT-ND genes; cardiolipin-associated ETC complexes.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human dopaminergic neurons carrying pathogenic NDUFV1 or NDUFV2 variants are treated with mitochondria-targeted coenzyme Q analogue (MitoQ) to scavenge complex I-derived superoxide, THEN mitochondr | Restored ΔΨm and increased ATP production in patient neurons with complex I variants | — no observation — | pending | 0.45 |
| IF cardiolipin peroxidation is specifically blocked in Ndufv2 knockdown mice via transgenic expression of cardiolipin-specific peroxidase (GPX4-cardiolipin fusion), THEN dopaminergic neuronal loss wil | Reduced neurodegeneration and slower functional decline when cardiolipin peroxidation is prevented despite complex I deficiency | — no observation — | pending | 0.40 |