Investigador: Isabel Antolin Rivera
Instituição:Grupo Metabolismos e Genética - Research Institute for Medicines (iMed.ILisboa), Faculdade de Farmácia da Universidade de Lisboa

Pyruvate is a key molecule in human metabolism once it links glycolysis to energy production via Krebs cycle and respiratory chain. Nevertheless, the pyruvate oxidation route is an intricate metabolic pathway as it encompasses all the steps mediating the passage of pyruvate from cytoplasm to mitochondrial matrix until its conversion to acetyl-CoA and, additionally, every step is regulated by specific proteins. Accordingly, an insufficient pyruvate turnover in mitochondria ussually originates severe clinical phenotypes.

Abstract
Pyruvate is a key molecule in human metabolism once it links glycolysis to energy production via Krebs cycle and respiratory chain. Nevertheless, the pyruvate oxidation route is an intricate metabolic pathway as it encompasses all the steps mediating the passage of pyruvate from cytoplasm to mitochondrial matrix until its conversion to acetyl-CoA and, additionally, every step is regulated by specific proteins. Accordingly, an insufficient pyruvate turnover in mitochondria ussually originates severe clinical phenotypes.

The first pathology to be known was pyruvate dehydrogenase complex (PDC) deficiency, once of the most challenging pathologies in terms of molecular diagnosis. Indeed, this complex is composed by three enzymatic subunits and one structural subunit, being also subjected to short-term regulation by phosphorylarion/dephosphorylation reactions. Globally, mutations in eleven different genes are responsible for the primary cause originating PDC deficiency.

Yet, it became soon evident that a significant number of patients remained without a comprehensive molecular diagnosis. But the advent during the last years of new-generation sequencing methodologies allowed to elucidation that the defects could also reside on genes encoding other proteins pivotal fora an efficient pyruvate conversion into acetyl-CoA. Effectively, it has been proved that those previously referred undiagnosed patients carried mutations in many cofactors necessary for PDC to achieve full activity. So, PDC deficiency can also be caused by secondary causes, what broadened to twenty-three the number of potentially mutant genes.

So, this project aims to identify the genetic defect underlying the PDC deficiency of a cohort of patients, until now undiagnosed at the molecular level. The results will contribute, not only for future genetic counseling in affected families, but especially to help clinicians to take the most adequate therapeutic measures, thus contributing for the patients better care and diseases prognosis.