Abstract
Impaired or deficient autophagy is believed to cause or contribute to aging, as well as a number of age-related pathologies. The exact mechanism through which alterations in autophagy induce these various pathologies is not well understood. Here we describe the creation of two in vivo mouse models that allow for the characterization of the alteration in mitochondrial function and the contribution of the corresponding oxidative stress following deletion of Atg7. Using these models we demonstrate that isolated mitochondria obtained from Atg7(-/-) skeletal muscle exhibit a significant defect in mitochondrial respiration. We further show that cells derived from Atg7(-/-) mice have an altered metabolic profile characterized by decreased resting mitochondrial oxygen consumption and a compensatory increase in basal glycolytic rates. Atg7(-/-)cells also exhibit evidence for increased steady state levels of reactive oxygen species. The observed mitochondrial dysfunction and oxidative stress is also evident in a mouse model where Atg7 is deleted within the pancreatic beta cell. In this model, the simple administration of an antioxidant can significantly ameliorate the physiological impairment in glucose-stimulated insulin secretion. Taken together, these results demonstrate the potential role of mitochondrial dysfunction and oxidative stress in autophagy related pathology.
Highlights
There is a growing interest in the role of macroautophagy, termed autophagy, in both normal homeostasis and in a variety of pathological conditions [1, 2]
In an effort to more fully characterize the role of autophagy in the maintenance of normal mitochondrial function, we created a conditional knockout model in which Atg7, an essential gene required for autophagosome formation, was deleted from mouse skeletal muscle
These results suggest that autophagy in skeletal muscle was largely impaired in these conditionally ablated animals, when compared to control animals, we observed no obvious differences in terms of viability, overall size and activity, serum parameters or generalized appearance of the Atg7F/F:muscle creatine kinase (MCK)-Cre mice throughout the first year of life
Summary
There is a growing interest in the role of macroautophagy, termed autophagy, in both normal homeostasis and in a variety of pathological conditions [1, 2]. This interest has been sparked in part by observations suggesting that in lower organisms, autophagy is an important determinant of lifespan [3]. In the worm, the increase in lifespan seen with dietary restriction is not evident when autophagy is impaired [6] Consistent with these observations, genetic manipulations that can increase autophagy in Drosophila result in flies with an extended lifespan and an increase in overall stress resistance [7]. Prior to the establishment of the molecular and biochemical basis for autophagy, www.impactaging.com
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