Antioxidant properties of UCP1 are evolutionarily conserved in mammals and buffer mitochondrial reactive oxygen species |
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| Institution: | 1. UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143-0669, USA;2. Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA;3. Institute for Diabetes, Obesity, and Metabolism, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA;1. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA;2. Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA;3. From the Dana-Farber Cancer Institute, Harvard Medical School and;4. Department of Cell Biology, Harvard University Medical School, Boston, Massachusetts 02115;1. Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany;2. Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany;3. Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, 53105 Bonn, Germany;4. Department of Animal Physiology, Philipps-Universität, 35043 Marburg, Germany;5. Department of Chemistry, Indiana University, Bloomington, 47405 IN, USA;1. Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, SE-405 30 Gothenburg, Sweden;2. Department of Biochemistry and Structural Biology, Centre for Molecular Protein Science, Lund University, Box 124, 221 00 Lund, Sweden;1. UCSF Diabetes Center, San Francisco, CA 94143, USA;2. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA 94143, USA;3. Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA;4. Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA;5. Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA;6. Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA |
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| Abstract: | Mitochondrial uncoupling reduces reactive oxygen species (ROS) production and appears to be important for cellular signaling/protection, making it a focus for the treatment of metabolic and age-related diseases. Whereas the physiological role of uncoupling protein 1 (UCP1) of brown adipose tissue is established for thermogenesis, the function of UCP1 in the reduction of ROS in cold-exposed animals is currently under debate. Here, we investigated the role of UCP1 in mitochondrial ROS handling in the Lesser hedgehog tenrec (Echinops telfairi), a unique protoendothermic Malagasy mammal with recently identified brown adipose tissue (BAT). We show that the reduction of ROS by UCP1 activity also occurs in BAT mitochondria of the tenrec, suggesting that the antioxidative role of UCP1 is an ancient mammalian trait. Our analysis shows that the quantity of UCP1 displays strong control over mitochondrial hydrogen peroxide release, whereas other factors, such as mild cold, nonshivering thermogenesis, oxidative capacity, and mitochondrial respiration, do not correlate. Furthermore, hydrogen peroxide release from recoupled BAT mitochondria was positively associated with mitochondrial membrane potential. These findings led to a model of UCP1 controlling mitochondrial ROS release and, presumably, being controlled by high membrane potential, as proposed in the canonical model of “mild uncoupling”. Our study further promotes a conserved role for UCP1 in the prevention of oxidative stress, which was presumably established during evolution before UCP1 was physiologically integrated into nonshivering thermogenesis. |
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| Keywords: | Afrotheria Brown adipose tissue Membrane potential Mild uncoupling Protoendothermic Reactive oxygen species Uncoupling protein 1 Evolution Free radicals |
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