Identification of genetic and environmental suppressors of mitochondrial dysfunction

Project Summary Mitochondrial diseases, or inherited disorders of oxidative phosphorylation, can be caused by mutations in at least 290 genes and affect approximately 1 in 5,000 live births. In addition to this collection of severe and individually rare disorders, mitochondrial dysfunction may underly many common diseases of aging, such as Parkinson’s and Alzheimer’s disease. The long-term goal of the applicant is to combine C. elegans genetics with techniques of mitochondrial physiology, biochemistry, and metabolism to identify novel genetic and environmental suppressors of mitochondrial dysfunction and elucidate the underlying mechanisms. Recent work has shown that hypoxia may be an effective treatment for loss of Complex I of the electron transport chain, however the precise molecular mechanism underlying the rescue by hypoxia remains elusive. In the first part of his postdoctoral training, the applicant has demonstrated that hypoxia can rescue another mitochondrial disease, Friedreich’s ataxia, which is caused by reduced levels of the Iron-Sulfur Cluster synthesis gene Frataxin. The applicant has performed forward genetic screens in C. elegans and identified five novel genetic suppressors of Frataxin and Complex I loss. In the K99/R00 application, the applicant proposes to (1) determine the mechanism underlying Complex I rescue by hypoxia, and (2) characterize the novel genetic suppressors of Complex I and Frataxin dysfunction. The applicant is jointly mentored by Drs. Gary Ruvkun and Vamsi Mootha in the MGH Molecular Biology Department. The Ruvkun lab will provide an excellent environment for C. elegans genetic analysis, and the Mootha lab will provide the candidate with new scientific training in mitochondrial physiology (e.g. NADH and oxygen consumption assays), biochemistry (e.g. blue native page), and metabolism (e.g. stable isotope tracer studies). In the K99 phase the applicant will also undertake coursework in Metabolism and Biochemistry, complementing the new scientific skillsets learned in the Mootha lab, and allowing him to start an independent research lab in the field of mitochondrial biology. Completion of the K99/R00 project will provide insights into basic mitochondrial biology and may lead to novel therapeutic strategies for mitigating mitochondrial disease.