Minimal mitochondrial respiration is required to prevent cell death by inhibition of mTOR signaling in CoQ-deficient cells
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Bibliographic record
Abstract
Coenzyme Q (CoQ) is a lipid-like mobile electron transporter of the mitochondrial respiratory chain. Patients with partial loss-of-function mutations in the CoQ biosynthesis pathway suffer from partial primary CoQ deficiency (MIM 607426). This leads to mitochondrial dysfunction, which presents like mitochondrial disease syndrome (MDS). In addition, many other conditions, including MDS itself, lead to secondary CoQ deficiency. We sought to identify drugs that can alleviate the consequences of the mitochondrial dysfunction that is associated with CoQ deficiency. Loss of the CoQ-biosynthetic enzyme COQ7 prevents CoQ synthesis but leads to the accumulation of the biosynthetic intermediate demethoxyubiquinone (DMQ). Coq7-knockout mouse embryonic fibroblasts (MEFs) die when rapid ATP generation from glycolysis is prevented. We screened for drugs that could rescue cell death under these conditions. All compounds that were identified inhibit mTOR signaling. In the CoQ-deficient cells, the beneficial action mTOR inhibition appears to be mediated by inhibition of protein translation rather than by stimulation of autophagy. We further studied the Coq7-knockout cells to better determine under which conditions mTOR inhibition could be beneficial. We established that Coq7-knockout cells remain capable of a low level of mitochondrial respiration mediated by DMQ. To obtain more profound mitochondrial dysfunction, we created double-knockout mutant MEFs lacking both Coq7, as well as Pdss2, which is required for sidechain synthesis. These cells make neither CoQ nor DMQ, and their extremely small residual respiration depends on uptake of CoQ from the culture medium. Although these cells are healthy in the presence of sufficient glucose for glycolysis and do not require uridine or pyruvate supplementation, mTOR inhibitors were unable to prevent their death in the absence of sufficient glycolysis. We conclude that, for reasons that remain to be elucidated, the energy-sparing benefits of the inhibition of mTOR signaling require a minimally functional respiratory chain.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it