Research Highlights

Our research centers on the mechanisms that enable the cell to take advantage of the high energetic yield of oxidative phosphorylation (OXPHOS) in spite of the concomitant production of reactive oxygen species (ROS). Defects in these mechanisms lead to energy depletion and oxidative damage, which are increasingly implicated in degenerative disease and aging.

Mitochondrial iron homeostasis is vital for OXPHOS maintenance and anti-oxidant protection. Both the heme and iron-sulfur cluster biosynthetic pathways depend on a constant supply of iron to the mitochondrial matrix, where micromolar concentrations of iron must be kept in reduced, available, and non-toxic form. This is a formidable challenge for the cell because the superoxide anion and hydrogen peroxide produced by the respiratory chain favor the iron-catalyzed production of the highly toxic hydroxyl radical.

Friedreich ataxia (FRDA) provides a dramatic example of what happens when mitochondria lose their ability to process iron properly. FRDA (http://www.ncbi.nlm.nih.gov/Omim) is a genetic degenerative disease that affects the central nervous system and the heart of children, adolescents and young adults, with a frequency of 1/40,000 newborns, corresponding to approximately 100 new cases per year in the US. Patients with FRDA suffer from progressive loss of neuronal and cardiac cells that result in wheelchair confinement, heart failure, and death at a young age. This devastating disease is caused by the lack of frataxin, a protein required to handle iron safely within the mitochondria.

We use FRDA as a model to understand mitochondrial iron balance and the consequences of defects in this process. My lab pioneered the study of frataxin and was the first to show that frataxin is an iron-binding protein. Our current research focuses on elucidating the mechanism of frataxin and identifying other mitochondrial proteins that cooperate with frataxin to maintain a functional OXPHOS and protect the cell from oxidative stress. In the long term, our basic studies will lead to rational treatments of FRDA and other OXPHOS-linked degenerative disorders.