TMET-16. ELUCIDATING MECHANISMS OF ENHANCED OXIDATIVE PHOSPHORYLATION IN MYC-AMPLIFIED MEDULLOBLASTOMA
Bibliographic record
Abstract
Abstract Medulloblastoma (MBL) is the most commonly diagnosed pediatric brain tumour and the leading cause of childhood cancer deaths. MYC overexpression often accompanies poor prognosis in MBL patients, as MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). However, it also induces a high metabolic demand that impairs cell survival under acute nutrient deprivation. We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, is overexpressed in MYC-driven MBL. Preliminary data suggests a relationship between eEF2K-mediated selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MBL. Multiplexed enhanced Protein Dynamic Mass Spectrometry was carried out in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. 9 of 10 detected components of the OXPHOS pathway were selectively translated in eEF2K-active MBL cells. Genetic eEF2K knockout led to the disassembly of electron transport chain (ETC) complexes I-V and reduced complex activity, as observed via Blue Native PAGE and colorimetric assays. Furthermore, siRNA knockdown of Cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial OXPHOS assembly factor differentially expressed in eEF2K active or inactive D425 cells, produces the same pattern of supercomplex (SC) loss as the inactivation of eEF2K in wild-type D425 cells. The assembly of ETC SC across D425 eEF2K active and inactive cells was further studied using blue native gel-based mass spectrometry to further characterize patterns in SC loss. In summary, control of translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MBL, likely representing an adaptive response against acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetics.
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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) | 0.000 | 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 | 0.000 | 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".