Adult mitochrondrial myopathy associated with generalized respiratory chain deficiency : molecular mechanism and genetic basis
Bibliographic record
Abstract
Cellular ATP is synthesized by the mitochondrial oxidative phosphorylation (OXPHOS) system, composed of five enzyme complexes (Complexes I--V), which consist collectively of over 80 subunits. The majority of these subunits are encoded by nuclear genes, and 13 of them, by mitochondrial DNA (mtDNA). OXPHOS deficiencies resulting in mitochondrial disorders can be caused by either nuclear or mitochondrial mutations; however, most pathogenic mutations reported in adults occur in mtDNA. Such mutations often impair mitochondrial translation and are associated with a characteristic muscle pathology consisting of a mosaic pattern of normal fibers interspersed with fibers displaying mitochondrial proliferation and decreased OXPHOS activity. In this thesis, the molecular basis for a severe mitochondrial myopathy in two adult patients was investigated. All patient muscle fibers showed mitochondrial proliferation and barely detectable Complex IV activity (a measure of OXPHOS activity), a pattern never before reported. Biochemical studies demonstrated decreased activities of Complexes I and IV (5% of control) and Complex II+III (41% of control) in patient muscle. Immunoblot analysis of nuclear and mitochondrial subunits of Complexes 1, III and IV showed a greater than 90% decrease in the steady-state level of these subunits in mature muscle, but no change in nuclear-encoded subunits of Complexes II and V. A generalized mitochondrial translation defect was identified by pulse-label experiments in myotubes, but not in myoblasts cultured from both patients. This defect moved with the nucleus in patient cybrid cells. Myoblasts from one patient transplanted into the muscle bed of SCID mice differentiated into mature muscle fibers that displayed a defect similar to that seen in the patient muscle. Mapping of the defective gene in this patient was attempted using a functional complementation approach. Microcell-mediated transfer of mouse chromosomes in patient
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".