Untargeted lipidomics to identify characteristic signatures and mechanisms of mitochondrial diseases according to genetic origin
Notice bibliographique
Résumé
Background: The major challenge in mitochondrial diseases relies in their great heterogeneity, in terms of genetic origin (i.e. nuclear or mitochondrial), mutation diversity and clinical manifestations. The underlying mechanisms are still unclear and often considered common to most mitochondrial diseases. Hypothesis: According to the genetic origin, the different lipidomic profiles will reveal common as well as mutation-dependent signatures. Aims: i) Establish the characteristic signatures of human fibroblasts from mitochondrial diseases of distinct genetic origins: either nuclear: LRPPRC and MTFMT, or mitochondrial: NDUFS4, UQCRC2 and ECHS1 compared with healthy fibroblasts and, based on the established signatures, ii) identify the underlying mechanisms. Methods: We used a mass spectrometry-based untargeted lipidomics approach to scan for thousands lipid signals. Based on the identified signatures, selected players were evaluated by quantitative PCR. Results: Principal component analysis shows that each cell line differs from the others. Our lipidomics analyses show that few lipids were modulated in a similar way irrespective of the genetic origin, and especially the increase in cholesterol esters. In contrast, ganglioside metabolism was differentially changed according to the genetic origin. More specifically, while GM3 forms were mostly and significantly increased for MTFMT, UQCRC2 and ECHS1 and moderately increased for NDUFS4, GM3 were decreased for LRPPRC. In addition, the GA1 and GM2 forms produced from GM3 were reduced in all cell lines except for LRPPRC and NDUFS4 where their signals remained unchanged. Since the formation of GA1 and GM2 involves the B4GALNT1 enzyme, we measured its mRNA expression and observed a drastic decrease up to 90% for MTFMT, while it remained unchanged for LRPPRC. Conclusion: The use of untargeted lipidomics is a relevant and powerful approach for the identification of specific signatures and underlying mechanisms of mitochondrial disorders, illustrated here by differentially affected ganglioside metabolism according to genetic origin, providing a starting point that will ultimately guide towards nutritional and therapeutic alternatives. Montreal Heart Institute Fundation, Lactic Acidosis Association and FRQS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».