The molecular basis by which dietary restricted feeding reduces mitochondrial reactive oxygen species generation

▶ The paper explains why mitochondria from DR rats generate lower rates of mitochondrial H 2O 2. ▶ Enhanced proton leak through the ANT induces mild uncoupling of the mitochondria in DR rats. ▶ The enhanced proton leak lowers the membrane potential and free radical generation rates. ▶ Proton leak th...

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Published in:	Mechanisms of ageing and development Vol. 132; no. 1; pp. 43 - 54
Main Authors:	Ash, C.E., Merry, B.J.
Format:	Journal Article
Language:	English
Published:	Shannon Elsevier Ireland Ltd 2011 Elsevier
Subjects:	Adenine nucleotide translocase Adipose Tissue, Brown - metabolism Animals Biological and medical sciences Caloric Restriction Development. Metamorphosis. Moult. Ageing Dietary restriction Fatty Acids, Nonesterified - blood Fundamental and applied biological sciences. Psychology Glucagon - blood Hydrogen Peroxide - metabolism Insulin Insulin - blood Insulin - pharmacology Ion Channels - metabolism Longevity - physiology Male Mitochondria Mitochondria - metabolism Mitochondria, Liver - metabolism Mitochondria, Muscle - metabolism Mitochondrial ADP, ATP Translocases - metabolism Mitochondrial Proteins - metabolism Oxygen Consumption Proton-Motive Force Rats Rats, Inbred BN Reactive Oxygen Species - metabolism ROS UCP1 Uncoupling Protein 1 Vertebrates: anatomy and physiology, studies on body, several organs or systems UCP1 Dietary restriction Mitochondria Insulin Adenine nucleotide translocase ROS Pancreatic hormone Reactive oxygen species Senescence Feeding behavior Feeding Vertebrata Generation Mammalia Restricted diet Adenine nucleotide
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Summary:	▶ The paper explains why mitochondria from DR rats generate lower rates of mitochondrial H 2O 2. ▶ Enhanced proton leak through the ANT induces mild uncoupling of the mitochondria in DR rats. ▶ The enhanced proton leak lowers the membrane potential and free radical generation rates. ▶ Proton leak through the ANT is induced by free fatty acids mobilized in response to DR feeding. ▶ The proton leak can be inhibited by exogenous insulin that inhibits free fatty acid mobilisation. Restricted feeding regimes in rodents that extend longevity lower the rate of mitochondrial reactive oxygen species generation. This effect is not dependent upon the depression of the state III and IV mitochondrial respiration rates. Mitochondria from liver, skeletal muscle and brown adipose tissue adapt to DR feeding with a lowered membrane potential that results from an enhanced proton leak across the inner membrane. Mitochondrial ROS generation is very sensitive to the magnitude of the membrane potential and the enhanced proton leak and ROS generation rates are reversible by exogenous insulin in liver and heart mitochondria. The adenine nucleotide translocase (ANT) was shown to be the dominant proton leak channel induced under DR feeding regimes in these tissues, while in brown fat mitochondria, UCP1 was activated, but this was not sensitive to exogenous insulin treatment. The effect of DR to modify the proton leak, membrane potential and ROS generation rate can be simulated by a range of non-esterified free fatty acids (NEFA) acting on the ANT to enhance its protonophoric activity. Mobilisation of NEFA under DR feeding, when insulin plasma concentrations are extremely low, explains the indirect action of insulin to counteract the effects of DR feeding on mitochondrial ROS generation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0047-6374 1872-6216
DOI:	10.1016/j.mad.2010.12.001