Replication data for: ATP synthase inhibition, an overlooked confounding factor in the mitochondrial stress test - statistical analysis supplement
Bibliographic record
Abstract
The mitochondrial stress test, a widely used procedure to study energy metabolism using extracellular flux analysis, involves the inhibition of ATP synthase (a.k.a. complex V [CV]). This inhibition was recently shown to cause a glycolysis-dependent underestimation of two key mitochondrial respiration parameters, maximal respiration (MR) and spare respiratory capacity (SRC), in tumor cells. However, it is unknown if test substances (toxins, drugs, signaling molecules, etc.), especially those affecting glycolysis, can impact the underestimation of MR and SRC caused by CV inhibition and thereby produce potentially erroneous results. The objective of the present study was to determine if the inhibition of CV in the mitochondrial stress test can act as a confounding factor when measuring MR and SRC in intact non-tumor cells exposed to exemplificatory test substances that affect energy metabolism: Ni2+ 56 and lipopolysaccharides (LPS). Murine bone marrow-derived macrophages were exposed to Ni2+ 57 (0–72 ppm) or LPS (1 µg/mL), and oxygen consumption rates were measured by extracellular flux analysis using the mitochondrial stress test, with and without CV inhibition. Results showed that CV inhibition masked the decrease in MR induced by Ni2+ 60 or LPS. It also caused the statistically non-significant decrease of SRC induced by Ni2+ 61 to present as an increase, and the LPS-induced decrease of SRC to be masked. Results also showed that these erroneous results arose because exposure to Ni2+ 62 and LPS reduced the underestimation of MR and SRC caused by CV inhibition. This phenomenon was associated with increased glycolytic. Finally, results confirmed that underestimation of MR and SRC induced by CV inhibition can occur in non-tumor cells. In conclusion, the present study demonstrates that CV inhibition can act as a confounding factor leading to erroneous conclusions when the mitochondrial stress test is used with intact cells exposed to test substances
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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 | 0.040 | 0.382 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.006 | 0.005 |
| Bibliometrics | 0.005 | 0.008 |
| Science and technology studies | 0.003 | 0.003 |
| Scholarly communication | 0.005 | 0.004 |
| Open science | 0.004 | 0.003 |
| Research integrity | 0.008 | 0.008 |
| Insufficient payload (model declined to judge) | 0.376 | 0.081 |
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".