Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation.
A major cause of aging and numerous diseases is thought to be cumulative oxidative stress, resulting from the production of reactive oxygen species (ROS) during respiration. Calorie restriction (CR), the most robust intervention to extend life span and ameliorate various diseases in mammals, reduces oxidative stress and damage. However, the underlying mechanism is unknown. Here, we show that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase. SIRT3 reduces cellular ROS levels dependent on superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. SIRT3 deacetylates two critical lysine residues on SOD2 and promotes its antioxidative activity. Importantly, the ability of SOD2 to reduce cellular ROS and promote oxidative stress resistance is greatly enhanced by SIRT3. Our studies identify a defense program that CR provokes to reduce oxidative stress and suggest approaches to combat aging and oxidative stress-related diseases.
Department of Nutritional Science & Toxicology, University of California, Berkeley, CA 94720, USA.
Xiaolei
X
Qiu
Katharine
K
Brown
Matthew D
MD
Hirschey
Eric
E
Verdin
Danica
D
Chen
D000107:Acetylation; D000818:Animals; D031204:Caloric Restriction; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000502:physiology*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009580:Nitroblue Tetrazolium; D018384:Oxidative Stress / Q000502:physiology*; D010269:Paraquat / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
D005978:Glutathione; D009580:Nitroblue Tetrazolium; D010269:Paraquat; D017382:Reactive Oxygen Species; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C525046:Sirt3 protein, mouse