Understanding ketogenesis in FRDA: Pathophysiology, biomarkers and nutritional therapies

The role of mitochondria in metabolism may mediate some components of FRDA, either in overall progression or in components such as diabetes. For example, platelets from patients with FRDA utilize fats in preference to sugars, suggestive of generalized metabolic dysfunction. Moreover, FRDA patients develop exercise intolerance, again suggesting that altered metabolism might play a role in the symptoms of FRDA. Understanding these events is important not only for creating new therapies for FRDA but also for the development of new markers. The relative inaccessibility of affected tissue in FRDA and the difficulty of measuring frataxin levels in vivo requires the development of novel biomarkers “close” to the events caused by frataxin loss. Metabolic and chemical imaging measurements of the markers in ketone utilization offer the possibility of providing such markers. Recent evidence from Dr. Lynch’s laboratory suggests a crucial role of metabolism of compounds called ketone bodies in the cause of FRDA. Frataxin controls ketone body metabolism through regulation of a specific enzyme, 3-Oxoacid CoA-Transferase 1 (OXCT1). This enzyme leads to the use of ketone bodies as energy. Dr. Lynch and his group found that frataxin physically interacts with OXCT1 and blocks its degradation, leading to failed ketone utilization when frataxin is not present. In this proposal, they will first define the diversity and significance of disruptions in ketone utilization in frataxin deficient cells. In addition, they will define the contribution of OXCT1 decreases to FRDA pathophysiology in animal models of FRDA. Finally, they will attempt to understand the role of abnormalities of ketone utilization in patients with FRDA. Collectively, these aims will determine the role of failed ketone utilization in features of FRDA.