Defining the short-term effects of pharmacological 5′-AMP activated kinase modulators on mitochondrial polarization, morphology and heterogeneity
Notice bibliographique
Résumé
BACKGROUND: Under aerobic growth conditions, mitochondria are the major producers of cellular ATP and crucial for the proper performance of organs and tissues. This applies especially to cells with high energy demand, such as the renal proximal tubule epithelium. Mitochondrial dysfunction contributes to the pathology of human health conditions, including various kidney diseases. The improvement of mitochondrial function ameliorates some of these pathologies. This can potentially be achieved with pharmacological compounds. For example, long-term treatment with activators of 5'-AMP activated kinase (AMPK) enhances mitochondrial biogenesis. However, pharmacological damage control during acute cell injury requires that the short-term effects of these compounds and the impact on healthy cells are also understood. It was our objective to define the changes elicited by established modulators of AMPK activity in healthy renal proximal tubule cells. METHODS: Our work combines confocal microscopy with quantitative image analysis, 3D image reconstruction and Western blotting to provide novel insights into the biology of mitochondria. Specifically, we evaluated the effects of pharmacological AMPK modulators (compound C, AICAR, phenformin, resveratrol) on mitochondrial polarization, morphology and heterogeneity. Microscopic studies generated information at the single cell and subcellular levels. Our research focused on LLC-PK1 cells that are derived from the renal proximal tubule. Mitochondrial heterogeneity was also examined in MCF7 breast cancer cells. RESULTS: Pharmacological agents that affect AMPK activity in renal proximal tubule cells can alter mitochondrial organization and the electrochemical potential across the inner mitochondrial membrane. These changes were compound-specific. Short-term incubation with the AMPK inhibitor compound C caused mitochondrial hyperpolarization. This was accompanied by mitochondrial fragmentation. By contrast, AMPK activators AICAR, phenformin and resveratrol had little impact. We further show that the biological properties of mitochondria are determined by their subcellular location. Mitochondria at the cell periphery displayed higher MitoTracker/Tom70 values as compared to organelles located in the vicinity of the nucleus. This was not limited to renal proximal tubule cells, but also observed in MCF7 cells. Pharmacological AMPK modulators altered these location-dependent properties in a compound-specific fashion. While the region-dependent differences were enhanced with phenformin, they were ameliorated by resveratrol. DISCUSSION: We evaluated the rapid changes in mitochondrial characteristics that are induced by pharmacological AMPK modulators. Our research supports the concept that pharmacological agents that target AMPK can rearrange mitochondrial networks at the single cell level. Collectively, these insights are relevant to the development of proper strategies for the short-term adjustment of mitochondrial performance.
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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) | 0,000 | 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 | 0,001 |
| 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 ».