Prohibitins are required for the induction of mitochondrial quality control mechanisms and the integrated stress response in skeletal muscle cells
Notice bibliographique
Résumé
Skeletal muscle health is dependent on the mitochondria that reside within it to maintain its function and metabolic flexibility. Chronic exercise has proven to be a potent intervention for the enhancement of the mitochondrial reticulum, indicating that training is a powerful strategy to improve muscle health. While our understanding of exercise-induced mitochondrial adaptations has been established, the key regulators underlying these processes remain underexplored. To investigate novel exercise-responsive mitochondrial regulators, a unique mitochondrial complex comprised of proteins Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2) were evaluated. Found within the inner mitochondrial membrane, PHBs have been implicated in several mitochondrial quality control (MQC) pathways, including biogenesis, mitophagy, and mitochondrial morphology, positioning them as critical regulators of mitochondrial function. Given the role of PHBs in various aspects of mitochondrial homeostasis, this would suggest that PHBs are required to mediate MQC pathways and permit exercise-induced mitochondrial adaptations. To examine this, PHB1 and PHB2 expression were targeted using short-interfering RNA within C2C12 myotubes and electrically stimulated for four days to induce contractile activity. Myotubes were then collected for protein measurements via western blotting techniques. Following a 56% reduction in both PHB1 and PHB2 protein, there was a marked decline in indicators of mitochondrial biogenesis, evident through a 38% reduction in mitochondrial transcription factor A (TFAM) and several mitochondrial-related proteins, including a 50% reduction in UQCRC2, a component of the electron transport chain. Mitochondrial fusion-related protein optic atrophy-1 (OPA-1) was significantly reduced, indicating that mitochondrial morphology is also affected with PHB silencing. These mitochondrial alterations were accompanied by the phosphorylation of eIF2α and upregulation of the transcription factor CHOP, which together are activated in response to cellular stress and dysfunction. Furthermore, a 3-fold increase in PINK1 protein was observed, indicating that the cellular stress observed may be mitochondrial-specific, as PINK1 is rapidly imported and degraded within healthy mitochondria. Contractile activity-induced mitochondrial adaptations were ablated with PHB knockdown, suggesting that PHBs may be required for the induction of MQC pathways by muscle contraction. These findings demonstrate that PHBs play a critical role in facilitating MQC, offering compelling new insight into the molecular mechanisms underpinning mitochondrial maintenance and adaptations observed in muscle with exercise. This work was supported by funds from the Natural Science and Engineering Research Council (NSERC). David A. Hood is the holder of a Canadian Research Chair in Cell Physiology. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
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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 | 0,001 | 0,001 |
| 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.
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