Eventos

Speaker: Dr. Nils-Göran Larsson M.D., Ph.D.  – Professor and Senior Consultant, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet  and Center for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital | Stockholm, Sweden.

Abstract: The components of the mammalian oxidative phosphorylation (OXPHOS) system have been studied in great molecular detail and consist of the respiratory chain enzyme complexes I-IV (CI-IV), the electron shuttles quinone (Q) and cytochrome c (Cyt c), and the ATP synthase. The respirasome represents a stable assembly of a complete respiratory chain (CI, CIII2, CIV).  Although respirasome formation is conserved in evolution, its role in physiology and disease is much debated. Mechanisms such as substrate channeling, reduction of reactive oxygen species production and adaptation to altered metabolic needs have been proposed. Unfortunately, the inability to selectively disrupt respirasome formation in vivo, has limited most studies to correlative and descriptive approaches. We have devised a knock-in strategy to selectively disrupt stable respirasome formation without impacting individual respiratory chain complexes in the mouse. This approach opens the field up to a series if critical experimental studies to define the enigmatic role for the respirasome in vivo. In an independent approach, we have shifted the balance between dehydrogenases feeding electrons into the Q pool by using a chemical inhibitor of the mitochondrial RNA polymerase to reduce mtDNA expression in the mouse. The treatment leads to a profound alteration of metabolism that promotes fatty acid oxidation in the liver.  Paradoxically, the reduced mtDNA expression is metabolically beneficial and counteracts obesity and diabetes.  The organization of the respiratory chain complexes and the balance between the different complexes has a role metabolic regulation that will be further discussed.