Mitochondrial-specific autophagy linked to mitochondrial dysfunction following traumatic freeze injury in mice
| Autor: | Luke J. Mortensen, Jarrod A. Call, Amelia Yin, Anna S. Nichenko, Grant H Mercer, Hang Yin, Alexandra B Flemington, Anita E. Qualls, William M. Southern, Kayvan Forouhesh Tehrani |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Mitochondrial Diseases Physiology Freeze injury Mitochondrial Proteins 03 medical and health sciences Mice 0302 clinical medicine Mitophagy medicine Autophagy Animals Autophagy-Related Protein-1 Homolog Muscle Skeletal business.industry Skeletal muscle Cell Differentiation Cell Biology Cell biology Mitochondria Mice Inbred C57BL Muscle regeneration 030104 developmental biology medicine.anatomical_structure Time course Wounds and Injuries Female business Microtubule-Associated Proteins 030217 neurology & neurosurgery Muscle Contraction Research Article |
| Zdroj: | Am J Physiol Cell Physiol |
| ISSN: | 1522-1563 |
| Popis: | The objective of this study was to interrogate the link between mitochondrial dysfunction and mitochondrial-specific autophagy in skeletal muscle. C57BL/6J mice were used to establish a time course of mitochondrial function and autophagy induction after fatigue ( n = 12), eccentric contraction-induced injury ( n = 20), or traumatic freeze injury (FI, n = 28); only FI resulted in a combination of mitochondrial dysfunction, i.e., decreased mitochondrial respiration, and autophagy induction. Moving forward, we tested the hypothesis that mitochondrial-specific autophagy is important for the timely recovery of mitochondrial function after FI. Following FI, there is a significant increase in several mitochondrial-specific autophagy-related protein contents including dynamin-related protein 1 (Drp1), BCL1 interacting protein (BNIP3), Pink1, and Parkin (~2-fold, P < 0.02). Also, mitochondrial-enriched fractions from FI muscles showed microtubule-associated protein light chain B1 (LC3)II colocalization suggesting autophagosome assembly around the damaged mitochondrial. Unc-51 like autophagy activating kinase (Ulk1) is considered necessary for mitochondrial-specific autophagy and herein we utilized a mouse model with Ulk1 deficiency in adult skeletal muscle ( myogenin-Cre). While Ulk1 knockouts had contractile weakness compared with littermate controls (−27%, P < 0.02), the recovery of mitochondrial function was not different, and this may be due in part to a partial rescue of Ulk1 protein content within the regenerating muscle tissue of knockouts from differentiated satellite cells in which Ulk1 was not genetically altered via myogenin-Cre. Lastly, autophagy flux was significantly less in injured versus uninjured muscles (−26%, P < 0.02) despite the increase in autophagy-related protein content. This suggests autophagy flux is not upregulated to match increases in autophagy machinery after injury and represents a potential bottleneck in the clearance of damaged mitochondria by autophagy. |
| Databáze: | OpenAIRE |
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