Nichenko, Anna S.;
Southern, W. Michael;
Tehrani, Kayvan Forouhesh;
Qualls, Anita E.;
Flemington, Alexandra B.;
Mercer, Grant H.;
Yin, Amelia;
Mortensen, Luke J.;
Yin, Hang;
Call, Jarrod A.
Mitochondrial-specific autophagy linked to mitochondrial dysfunction following traumatic freeze injury in mice
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Media type:
E-Article
Title:
Mitochondrial-specific autophagy linked to mitochondrial dysfunction following traumatic freeze injury in mice
Contributor:
Nichenko, Anna S.;
Southern, W. Michael;
Tehrani, Kayvan Forouhesh;
Qualls, Anita E.;
Flemington, Alexandra B.;
Mercer, Grant H.;
Yin, Amelia;
Mortensen, Luke J.;
Yin, Hang;
Call, Jarrod A.
Published:
American Physiological Society, 2020
Published in:
American Journal of Physiology-Cell Physiology, 318 (2020) 2, Seite C242-C252
Language:
English
DOI:
10.1152/ajpcell.00123.2019
ISSN:
0363-6143;
1522-1563
Origination:
Footnote:
Description:
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.