Kyle Bryant Translational Research Award

Gino A. Cortopassi, PhD

University of California, Davis
Screening for mitofunctional Friedreich’s Ataxia therapeutics

Mutations in the frataxin gene result in defects in mitochondrial function that are the likeliest cause of neuro- and cardiodegeneration in the movement disorder Friedreich’s ataxia. Currently there is no curative therapy for Friedreich’s ataxia specifically and for mitochondrial disease in general. We have recently improved an assay with which to screen thousands of compounds for their positive effect on mitochondrial function, based on mitochondrial Oxygen (O2) consumption. We have constructed a cell line in which frataxin is inhibited, and show that mitochondrial O2consumption is decreased. We have accumulated other cell models of mitochondrial disease, i.e. cells bearing mitochondrial mutations, and these cell models also exhibit decreased mitochondrial O2 consumption. Thus our goal is to screen large drug libraries to identify drugs that increase mitochondrial O2 consumption and rescue mitochondrial deficits that are the specific consequence of deficits in frataxin. As a positive test of the assay, we demonstrate that known chemical inducers of mitochondrial function (FCCP) and mitochondrial biogenesis (rosiglitazone, resveratrol, bezafibrate) are detected by the assay. Thus we will screen large drug libraries to identify compounds that enhance the function of mitochondria compromised by deficiencies of frataxin. These drug leads might serve as the progenitors of effective small-molecule therapy for Friedreich’s ataxia.