The research of Grazia Isaya, M.D., Ph.D., centers on the mechanisms that enable the cell to take advantage of the high energetic yield of oxidative phosphorylation in spite of the concomitant production of reactive oxygen species. 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 oxidative phosphorylation maintenance and antioxidant 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 nontoxic 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's ataxia provides a dramatic example of what happens when mitochondria lose their ability to process iron properly. Friedrich's ataxia 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 in 40,000 newborns, corresponding to approximately 100 new cases a year in the U.S.
Patients with Friedreich's ataxia have progressive loss of neuronal and cardiac cells that results in wheelchair use, 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.
- Frataxin function in oxidative phosphorylation. Dr. Isaya's research team uses Friedreich's ataxia as a model to understand mitochondrial iron balance and the consequences of defects in this process. Her lab pioneered the study of frataxin and was the first to show that frataxin is an iron-binding protein. Current research focuses on elucidating the mechanism of frataxin and identifying other mitochondrial proteins that cooperate with frataxin to maintain a functional oxidative phosphorylation and protect the cell from oxidative stress.
Significance to patient care
In the long term, the basic studies carried out in Dr. Isaya's lab will lead to rational treatments of Friedreich's ataxia and other degenerative disorders linked to oxidative phosphorylation.