Effects of N‐oleoylethanolamide on Lymphoblasts Deficient in Tafazzin
Bibliographic record
Abstract
Barth Syndrome (BTHS) is a rare X‐linked genetic disorder caused by mutations in the TAZ gene that encodes for the cardiolipin remodelling enzyme, Tafazzin. This syndrome is characterized by cardiac and skeletal myopathies, as well as immunological deficits that cause significant morbidity and mortality. Study of the molecular pathology of BTHS thus provides insight into the role of cardiolipin and mitochondria in cellular physiology, while addressing a clinically relevant disease. Current treatment options for BTHS are limited, but a recent trial suggests that PPARα activation may be therapeutic. The objective of this study was to quantitatively examine the growth properties and mitochondrial physiology of B‐lymphoblasts derived from five donors with BTHS, as well as effects of treatment with oleoylethanolamide (OEA), a bioactive N‐acylethanolamine. Cyclic neutropenia is a well‐recognized aspect of the pathology of BTHS. We hypothesized that deficits in lymphoblast proliferation would also be evident, and that OEA, which activates receptors including PPARα, would demonstrate therapeutic benefit. One million B‐lymphoblasts derived from BTHS donors and age‐ and sex‐matched healthy controls were seeded on day 0 and counted daily for 4 days. On day 4, there were 27.7 ± 4.6% fewer BTHS B‐lymphoblasts than control cells (P<0.05), indicating that lymphopenia is likely also a component of BTHS. Treatment of B‐lymphoblasts with 1 μM OEA caused no significant effect on control cell numbers, but significantly improved deficits in each of the five BTHS lymphoblast lines, raising the mean cell number on day 4 from 3.74 × 10 6 to 4.25 × 10 6 cells, although a full rescue of growth was not achieved. Analysis of electron micrographs of samples from two distinct BTHS B‐lymphoblast donors indicated that cells had larger mitochondria as compared with healthy controls (mean of 0.67 ± 0.07 µM 2 versus 0.27 ± 0.16 µM 2 , respectively). OEA decreased mitochondrial size by 53.0 ± 10.9%, while increasing the total mitochondrial number per cell by 92.6 ± 58.6%. OEA reduced the elevated expression of the enzyme CDS1 in BTHS B‐lymphoblasts to healthy control levels, suggesting improved cardiolipin levels may play a role. However, an initial donor pair comparison did not show an effect of OEA on cardiolipin content, suggesting other mechanisms should be explored. Higher immunodetectable levels of OPA1, a biomarker of mitochondrial fusion, were found in lymphoblasts from children with BTHS, and were attenuated by OEA. Results from this study newly identify lymphopenia as a probable immunological deficit in BTHS, and suggest that therapies targeting aberrant fission/fusion of the mitochondrial network, rather than cardiolipin content, per se, and may have clinical utility for treatment of this disease.
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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".