Mitochondrial uncoupling prevents cold-induced oxidative stress: a case study using UCP1 knock-out mice

Abstract

Summary The relationship between metabolism and reactive oxygen species (ROS) production by the mitochondria has been often (wrongly) viewed as straightforward, with increased metabolism leading to higher pro-oxidants generation. Insights on mitochondrial functioning show that oxygen consumption is either principally coupled with energy conversion as ATP or as heat, depending on whether the ATP-synthase or the mitochondrial uncoupling protein 1 (UCP1) is driving respiration. However, those two processes might greatly differ in terms of oxidative costs. We used a cold challenge to investigate the oxidative stress consequences of an increased metabolism achieved either by the activation of an uncoupled mechanism (i.e. UCP1 activity) in the brown adipose tissue (BAT) of wild-type mice, or by ATP-dependent muscular shivering thermogenesis in mice deficient for UCP1. Although both mouse strains increased by more than twofold their metabolism when acclimatised for 4 weeks to moderate cold (12°C), only mice deficient for UCP1 suffered from elevated levels of oxidative stress. When exposed to cold, mice deficient for UCP1 showed an increase of 20.2% in plasmatic reactive oxygen metabolites, 81.8% in muscular oxidized glutathione and 47.1% in muscular protein carbonyls. In contrast, there was no evidence of elevated levels of oxidative stress in the plasma, muscles or BAT of wild-type mice exposed to cold despite a drastic increase in BAT activity. Our study demonstrates differing oxidative costs linked to the functioning of two highly metabolically active organs during thermogenesis. It urges for careful considerations of mitochondrial functioning when investigating the links between metabolism and oxidative stress. Although both mouse strains increased by more than twofold their energy expenditure when acclimatised for 4 weeks to mild cold (12°C), only mice deficient for UCP1 suffered from elevated levels of oxidative stress. When exposed to cold, mice deficient for UCP1 showed an increase of 20.2% in plasmatic reactive oxygen metabolites, 81.8% in muscular oxidized glutathione and 47.1% in muscular protein carbonyls. In contrast, there was no evidence of elevated levels of oxidative stress in the plasma, muscles or BAT of wild-type mice exposed to cold despite a drastic increase in BAT activity. Our study demonstrates differing oxidative costs linked to the functioning of two highly metabolically active organs during thermogenesis. It urges for careful considerations of mitochondrial functioning when studying/considering the links between energy expenditure and oxidative stress.