ID: h-c1f19a34
Hypothesis
A genetically encoded reporter for axonal mitochondrial protein import fidelity as a biomarker of compartmentalization
MTS-dGFP fusion construct requires intact TOM40/TOM20 translocase for mitochondrial import, serving as direct read-out of compartmentalized proteostasis capacity.
🧬 TOM20, TOM40 (translocase complex); CHOP/DDIT3 (stress response promoter)🩺 neuroscience🎯 Composite 57%💱 $0.57▼12.1%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 3 oppose
✓ All Quality Gates Passed
🧪 Overview
MTS-dGFP fusion construct requires intact TOM40/TOM20 translocase for mitochondrial import, serving as direct read-out of compartmentalized proteostasis capacity. CHOP promoter-driven alternative fluorophore provides stress-responsive signal. Cryo-EM of import pores in same cells anchors ratiometric imaging to ultrastructure. Primary flaw: reporter fails entirely when import machinery is impaired (ceiling effect), generating false-negatives indistinguishable from severe pathology.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["TOM20/TOM40 Translocase<br/>Outer Membrane Import Gateway"]
B["MTS-dGFP Cargo Entry<br/>Presequence-Dependent Import Flux"]
C["Matrix Delivery Readout<br/>Compartmentalized Proteostasis Capacity"]
D["CHOP/DDIT3 Stress Promoter<br/>Import Failure Alarm Signal"]
E["Axonal Mitochondrial Quality Loss<br/>Proteotoxic Burden Rises"]
F["Biomarker of Import Collapse<br/>Neurodegeneration Risk Reported"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix3 supports3 contradicts
Contradicts
TOM40 dysfunction is downstream of TDP-43 aggregation; global mitochondrial defects, not compartment-specific
Contradicts
TOMM20 immunoreactivity measures protein abundance, not import fidelity; cannot distinguish functional from non-functional import capacity
Contradicts
Mitochondrial defects are consequence of compartmentalization breakdown, not direct measure of it
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TOM20
No curated PDB or AlphaFold mapping for TOM20 yet. Search RCSB →
💉 Clinical Trials
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 TOM20, TOM40 (translocase complex); CHOP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
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📊 Market Indicators
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary cortical neurons from 6-month-old App<sup>NL-G-F</sup> knock-in mice (Alzheimer's model) are transfected with the MTS-dGFP reporter at DIV 14, THEN axonal mitochondrial dGFP fluorescence in | Significant reduction in MTS-dGFP signal specifically in axonal mitochondria of AD model neurons, reflecting impaired TOM40/TOM20-dependent import | — no observation — | pending | 0.62 |
| IF SH-SY5Y cells are pre-treated with 200 nM thapsigargin for 6 hours to induce ER stress, THEN CHOP-DsRed fluorescence will increase ≥3-fold while MTS-dGFP remains detectable above background (mean i | ER stress induces CHOP signal without abolishing dGFP import, whereas ATP depletion abolishes dGFP import entirely due to import machinery failure | — no observation — | pending | 0.58 |
🔮 Falsifiable Predictions (2)
pendingconf 62%
IF primary cortical neurons from 6-month-old App<sup>NL-G-F</sup> knock-in mice (Alzheimer's model) are transfected with the MTS-dGFP reporter at DIV 14, THEN axonal mitochondrial dGFP fluorescence intensity will be reduced by ≥40% compared to age-matched wild-type littermate controls within 72 hour
Predicted outcome: Significant reduction in MTS-dGFP signal specifically in axonal mitochondria of AD model neurons, reflecting impaired TOM40/TOM20-dependent import
Falsification: No statistically significant difference (p>0.05) in axonal mitochondrial dGFP intensity between App<sup>NL-G-F</sup> and wild-type neurons, or paradoxical increase in signal, would falsify the hypothe
pendingconf 58%
IF SH-SY5Y cells are pre-treated with 200 nM thapsigargin for 6 hours to induce ER stress, THEN CHOP-DsRed fluorescence will increase ≥3-fold while MTS-dGFP remains detectable above background (mean intensity >500 a.u.), indicating the stress-responsive fluorophore provides a compensatory read-out w
Predicted outcome: ER stress induces CHOP signal without abolishing dGFP import, whereas ATP depletion abolishes dGFP import entirely due to import machinery failure
Falsification: If thapsigargin also abolishes dGFP signal completely, or if oligomycin A induces proportional CHOP upregulation, the compensatory relationship between the two fluorophores does not hold, falsifying t
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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