Molecular mechanisms of pathogenicity in ATP synthase disorders

Mutations in mitochondrial FoF1 ATP synthase responsible for severe inborn errors of metabolism. One of the striking features is the tissue specificity of symptoms associated with mutations in individual subunits. Recently, we have developed animal models for two genes causing ATP synthase disorder – Tmem70 and Usmg5. The aim of this project is to explore differences in tissue presentation as well as compensatory or regulatory mechanisms involved to mitigate pathogenic phenotype.

Targeting mitochondrial fatty acid oxidation and adipose tissue browning to prevent obesity

Obesity is a major risk factor for metabolic disorders such as type diabetes, hypertension, and cardiovascular diseases. From the recent discoveries, hormonal treatment or browning of white fat cells are most friendly to the patients. The browning is accompanied by mitochondrial biogenesis and increased fatty acid oxidation capacity. Therefore, we aim to study the role of mitochondrial proteins in browning of subcutaneous adipose tissue and to uncover their potential for treating the obesity.

Adaptations of cellular metabolism to dysfunction of mitochondrial oxidative phosphorylation

Defects of oxidative phosphorylation (OXPHOS) lead to severe diseases, affecting tissues with high energetic demands. In order to survive, diseased cells need to reconfigure their metabolic pathways. In this project, we will study mammalian models with primary defects of OXPHOS using modern metabolomic and proteomic approaches. We aim to identify metabolic fingerprints in the models that would allow us to define key metabolic pathways that could be used as therapeutic targets in the future.

The role of SURF1 protein in biogenesis of mammalian cytochrome c oxidase

Cytochrome c oxidase (COX) is a key enzyme of mitochondrial energetics. Assembly of 14 COX subunits depends on numerous ancillary factors, including SURF1 implicated in insertion of heme a into the enzyme. We hypothesize that SURF1 represents an adaptor protein between heme a synthesis enzymes and COX1, cooperating with assembly factors PET117 and Coa2 to secure insertion of proper heme type. New data on COX biogenesis may contribute to therapy of SURF1-associated neurodegeneration disease.