Mitochondrial Genetics - Grazia Isaya

Research

Mitochondrial oxidative phosphorylation (OXPHOS) is the main source of ATP for the eukaryotic cell.

OXPHOS, however, is also the main source of reactive oxygen species (ROS).

As it turns out, OXPHOS is the most immediate target of ROS attack because biomolecules essential for OXPHOS activity such as mitochondrial DNA and iron-sulfur proteins are exquisitely susceptible to oxidative damage. This situation is exacerbated by the fact that OXPHOS biogenesis requires a continuous supply of iron-sulfur clusters and heme, which in turn depends on the availability of Fe²⁺, and redox-active iron can catalyze production of hydroxyl radical, the most reactive oxygen species known.

Our lab is interested in the mechanisms that enable the cell to exploit the energy efficiency of OXPHOS in spite of the risks inherent in ROS production. In particular, we are interested in the role played by mitochondrial proteins involved in iron homeostasis.

Approach

• Screen for nuclear genes involved in OXPHOS maintenance in S. cerevisiae and identify their human and mouse homologues
• Create yeast and mouse mutants with complete or partial inactivation of these genes and extrapolate the function of the encoded proteins
• Express wild type and mutant forms of these proteins in E. coli and elucidate their mechanism of action in cell free systems

Long-term Goals of Our Research

OXPHOS defects are a frequent and important cause of disease. They affect primarily pediatric patients but can present at virtually all ages with a wide variety of clinical manifestations ranging from multisystemic mitochondrial cytopathies to neurodegenerative diseases (e.g. Friedreich ataxia). By expanding the knowledge of the mechanisms responsible for OXPHOS maintenance, we hope to contribute to the molecular and biochemical characterization of these conditions and the development of effective treatments.