Leigh Syndrome French Canadian Type Patient Fibroblasts Exhibit Energy Metabolism Adaptations Through a Warburg‐like Effect
Bibliographic record
Abstract
Background & Objective LSFC is a recessive mitochondrial disease caused by mutations in the LRPPRC gene resulting in a decrease in the LRPPRC protein. This leads to a tissue‐specific reduction of complex IV or cytochrome c oxidase (COX). Our previous work in LSFC fibroblasts demonstrated several mitochondrial functional abnormalities including reduced mitochondrial membrane potential, fragmentation of the mitochondrial network and impaired oxidative phosphorylation capacity. Despite these abnormalities, LSFC fibroblasts did not display any reduction in ATP levels, suggesting the activation of compensatory mechanisms. We hypothesized that mTORC1‐mediated glycolytic ATP production, also known as Warburg effect, might compensate for mitochondrial dysfunction. To address this question, we evaluated glycolytic flux and the Akt/mTORC1 signaling pathway, using LSFC and control skin fibroblasts as a model. Results Our results showed numerous adaptations of LSFC energy metabolism. Metabolic flux analysis revealed that glucose contribution to pyruvate, lactate and alanine formation was respectively increased by 41%, 61%, and 52% (p≤0.05) in LSFC fibroblasts compared to controls. At the molecular level, the Akt/mTORC1 pathway was up regulated in LSFC cells compared to controls (pAkt 111%, p≤0.05; Akt 44%, p≤0.001; mTOR 51%, p≤0.01). This includes enhanced phosphorylation of mTORC1 downstream targets p70S6K by 105% (p≤0.05); as well as an increase in the expression of the transcription factor HIF‐1α by 200% (p≤0.01). The level of pyruvate dehydrogenase kinase 1 (PDHK1), a HIF‐1α downstream target and an inhibitor of mitochondrial glucose oxidation via pyruvate dehydrogenase 1 (PDH1) phosphorylation, was also up regulated by 150% (p≤0.05) in LSFC cells. Consistent with these results, we observed an increase of PDH1 phosphorylation by 94% (p≤0.01) in LSFC cells compared to controls. To further delineate the role of mTORC1 pathway in these adaptations, we inhibited its activity with rapamycin. mTORC1 inhibition did not affect HIF‐1α or PDHK1 expression. However, rapamycin was associated with increased PDH1 phosphorylation (p≤0.05) by 37% and 42% in LSFC and control fibroblasts, respectively. Rapamycin also reduced ATP levels by 8% (p=0.07) in LSFC fibroblasts comparatively to 15% (p≤0.05) in controls. Interestingly, rapamycin decreased LRPPRC expression by 41% (p≤0.01) in LSFC cells compared to only 11% (p≤0.05) reduction in control. This was associated with a selective reduction of COX expression in LSFC (32%, p≤0.01) fibroblasts, while we did not observe any change in expression of the others mitochondrial complexes. Conclusion LSFC fibroblasts maintain ATP levels probably through a “Warburg‐like effect”; for which mTORC1 is not the primary regulator. mTORC1 activation, however, appears important for LRPPRC and therefore, COX expression in LSFC fibroblasts. Support or Funding Information Supported by: Association de l'acidose lactique and CIHR Emerging Team Grant
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 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) | 0.006 | 0.001 |
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".