Harper 2018 MiPschool Tromso E1
Harper ME (2018)
Event: MiPschool Tromso-Bergen 2018
In some small mammals, the activation of brown adipose tissue (BAT) can cause a doubling of resting metabolic rate. This remarkable increase in whole body oxygen consumption and thermogenesis relies heavily on uncoupling protein-1 (UCP1) which is expressed in BAT and in beige adipose tissue. The capacity of BAT for such high rates of oxygen consumption and thermogenesis stems from 1) a dense mitochondrial network in BAT, 2) a very high amount of UCP1 per unit mitochondrial protein (10%), and 3) extensive capillary networks and arteriovenous anastomoses that rapidly efflux heat into the blood circulation. When BAT is activated the major sources of fuel are fatty acids, which are oxidized by beta-oxidation, and the ensuing reducing equivalents/electrons then drive electron transport system (ETS) activity. These oxidative reactions are responsible for the actual thermogenesis. Importantly, fatty acids also activate UCP1 protein, and this is thought to occur through interfering with purine nucleotide inhibition of UCP1. When UCP1 is active, it allows protons to leak back into the mitochondrial matrix; this stimulates ETS activity because it removes the back-pressure of proton motive force, that would otherwise prevent ETS activity. In other words, it removes the brakes on the system, and uncoupled respiration can occur at very high rates.
Despite the recent excitement emanating from the discovery that BAT is present in adult humans, there is only a rudimentary understanding of the mechanisms that turn BAT on and off. Recent developments in the area of BAT have focused on 1) characterizing the amount of active BAT in adult humans, 2) brown fat adipogenesis and the common cellular origins of brown adipocytes and muscle cells, 3) the mechanisms through which beige adipose tissue develops and is activated, and 4) the role of redox and reactive oxygen species (ROS) in the activation of UCP1 in BAT. One aspect of BAT physiology that is not well understood is the role of deacetylation control of BAT mitochondrial energetics and thermogenesis. Indeed, the role of post-translational control of BAT proteins in general is poorly understood. We reasoned, given that fatty acid oxidation is exceptionally high in active BAT, it would be informative to examine the impact of mitochondrial protein acetylation in active versus inactive BAT in the presence and absence of the mitochondrial deacetylase, SIRT3. It is well known that the acetylation of mitochondrial proteins can be particularly high when rates of fatty acid oxidation are high, due to the high rates of acetyl CoA production. Acetylation status of BAT mitochondrial proteins was investigated using label-free acetylomics. We quantified over 2000 acetylation sites, and our findings from acetylome profiling in BAT mitochondria, and corresponding functional assays will be described.
- Mitochondrial Bioenergetics Lab, Dept Biochemistry, Microbiology Immunology, Fac Medicine, Univ Ottawa, ON, Canada.
Regulation: Fatty acid