Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy.
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.
Wu
J Julie
JJ
Translational Medicine Branch, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Quijano
Celia
C
Chen
Edmund
E
Liu
Hongjun
H
Cao
Liu
L
Fergusson
Maria M
MM
Rovira
Ilsa I
II
Gutkind
Sarah
S
Daniels
Mathew P
MP
Komatsu
Masaaki
M
Finkel
Toren
T
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*
C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D000071193:Autophagy-Related Protein 7; D005947:Glucose