Sustained shivering induces adaptive mitochondrial mechanisms to buffer increased oxidative stress and maintain energy metabolism

Abstract

Eutherian mammals evolved thermogenic uncoupling protein 1 (UCP1) in brown adipose tissue mitochondria to defend body temperature in the cold by non-shivering thermogenesis replacing shivering thermogenesis [1]. UCP1 knockout (UCP1-KO) mice rely on sustained shivering in the cold but their skeletal muscle mitochondria exhibit neither dysfunction of respiration nor pronounced oxidative damage [2, 3]. Here, we studied mitochondrial reactive oxygen species (ROS) handling of muscle mitochondria from wildtype and UCP1-KO mice. We find that prolonged cold exposure increases hydrogen peroxide release rates in isolated UCP1-KO mice mitochondria, which is partially blunted by increased adenine nucleotide translocase (ANT) function. The physiological significance of deleterious ROS production during sustained shivering was further substantiated by activity of mitochondrial aconitase, a TCA cycle enzyme that is gradually inactivated by ROS. Our mouse model elucidates adaptive molecular responses to maintain mitochondrial function in muscle during sustained shivering and to buffer increased mitochondrial ROS production.