Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals

摘要

Currently there is great interest in determining the meaningful purposes that autophagy has in regulating cellular health, and in more fully understanding the factors that direct selective forms of autophagy, such as mitophagy, which is autophagy-mediated mitochondrial turnover. Autophagy signaling is initiated in response to a multitude of factors including nutrient deprivation (12, 13, 25, 37) or oxidative stress (6, 18, 24, 31). Initiation of autophagy involves the activation of the unc-51 like kinase (ULK1)/ATG1 complex, which has been shown to be conserved in skeletal muscle (30), and the Beclinl/vacuole protein sorting/PI3K complex, respectively. These operate in conjunction to mediate the initial assembly of the autophago-somal membrane (4, 19). The maturation and completion of the autophagosome is facilitated by a separate ubiquitin-like conjugation signaling cascade that culminates with the microtu-bule-associated protein 1 light chain 3 (MAP-LC3) incorporation of phosphatidylethanolamine into autophagosome membranes (4). Upon completion, the contents encased in mature autophagosomes are degraded by a battery of lysosomal hy-drolases into macromolecules and then released into the cytoplasm (20, 21, 28).