Mitochondrial uncoupling and remodelling during caloric restriction: Implications for oxidative stress and aging

Abstract

The 'uncoupling to survive' theory suggests that mitochondrial uncoupling protects cells from reactive oxygen species (ROS), thereby slowing aging. Caloric restriction (CR) mitigates aging; mechanisms may involve mitochondrial remodelling such that ROS production is decreased. It is unclear how uncoupling protein 3 (UCP3) in skeletal muscle is involved. Objective: To characterize effects of short-term 40% CR in wildtype (Wt) and UCP3 transgenic (UCP3 Tg) mice that possess uncoupled mitochondria. Hypothesis: In an uncoupled system, CR provides no further ROS protection. Approaches: Muscle mitochondrial and whole body assessments of UCP3's contribution to uncoupling and oxidative stress. Results: UCP3 Tg mice had lower body (P<0.001) and muscle weight (P<0.01), increased energy expenditure (P=0.12), similar body composition, increased proton leak (P<0.05), and decreased ROS production (P<0.05). In Wt mice, 1 mo CR mitigated ROS production (P<0.05), increased proton leak (P<0.05), decreased oxidative capacity (P<0.01), and increased UCP3 (P<0.05) protein levels. Such changes were not observed in UCP3 Tg mice. Overall, findings indicate that uncoupling in muscle does not reflect a pre-adaptation to CR. Rather, uncoupling delays the adaptive mitochondrial remodelling normally induced by short-term CR.