A Reduction in Tafazzin Decreases Mitochondrial Function in C2C12 Myotubes
Notice bibliographique
Résumé
Mitochondria, which are often regarded as the “powerhouse of the cell”, are labile organelles that regulate cellular metabolism, determine cell fate, and act as important signaling hubs. A phospholipid that is exclusively found within mitochondria that serves numerous roles is cardiolipin (CL). In healthy mitochondria, CL is predominately localized in the inner mitochondrial membrane (IMM) and binds to several membrane proteins including those in the electron transport chain (ETC) and in the protein import machinery (PIM). Similarly, CL has also been shown to regulate cell death and mitophagy in dysfunctional mitochondria. Following the biosynthesis of nascent CL in the inner membrane, it is remodeled into its mature form by a transacylase, tafazzin (Taz). The absence of this enzyme is associated with Barth Syndrome, a disease characterized by cardiomyopathy and skeletal myopathy. Interestingly, little is known about the role of mature CL in skeletal muscle. Therefore, the objective of this study was to identify whether Taz deficiency diminishes mitochondrial function in the presence or absence of changes in organelle volume and function. We hypothesized that a reduction in Taz will attenuate mitochondrial function, while lysosomal and mitochondrial content will be elevated. To test this hypothesis, C2C12 myotubes were transfected on day 3 of differentiation with either a scrambled or Taz siRNA vector. Cells were harvested for analysis on day 7 of differentiation. Organelle volume was assessed using immunohistochemistry and Western blot techniques, whereas Seahorse technology was used to measure mitochondrial respiration. In comparison to C2C12 myotubes that were treated with a scrambled vector, Taz protein content was reduced by 85% (P<0.05) in siRNA‐treated cells. Maximal oxygen consumption and ATP production were attenuated in Taz‐deficient cells by 18% and 14%, respectively, while basal respiration remained unaffected. Lysosome and mitochondrial content were increased 20% and 24%, respectively, in Taz‐deficient cells. Similarly, myotubes lacking Taz exhibited a 7% increase (P=0.056) in Complex IV protein content, but lysosomal‐associated membrane protein 1 (LAMP1) decreased 33% (P<0.05). Myosin heavy chain (MHC) IIX was also elevated by 32% in mature CL depleted myotubes. CL‐deficient myotubes were 32% smaller in diameter and 10% longer when compared to scrambled treated myotubes. These data suggest that a reduction in mature CL impairs skeletal muscle mitochondrial function. Moreover, although lysosomal content was elevated, lysosomes appear to have a reduced capacity to fuse with autophagosomes, which may in part explain why there is an increase in dysfunctional mitochondria. Future research should evaluate mitophagy flux and mitochondrial membrane potential in the presence of reduced mature CL in C2C12 myotubes, and whether exercise has the ability to rescue mitochondrial function.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».