ATPIF1 inhibition as a therapeutic strategy for mitochondrial dysfunction

Harvard Medical School, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): It is now well-appreciated that mitochondrial dysfunction can play an important role in the process of aging, as well as the pathology of age-related diseases, such as Parkinson's Disease (PD). Despite our improved understanding of the molecular mechanisms underlying mitochondrial derangement, there is a paucity of effective treatments, largely because few therapeutic targets have been identified.1 To address this issue, a powerful new haploid genetic screening platform in human cells2 was used to identify genes, loss-of-function of which could confer resistance to mitochondrial dysfunction induced by antimycin, a mitochondrial toxin. Treatment of cells with antimycin mimics the pathology of many different mitochondrial disease states and thus the genes identified in this screen could be novel therapeutic targets. To investigate the potential mechanisms of resistance associated with specific gene loss, relevant aspects of mitochondrial physiology, such as mass, respiratory activity, membrane potential, and reactive oxygen species generation, will be assessed. Importantly, the potential of each gene in conferring resistance to disease phenotypes will be studied in three different systems: cell lines treated with pharmacological inhibitors of mitochondrial function; cell lines derived from patients with mitochondrial disorders; and mouse models of mitochondrial dysfunction, such as PD. It is our hope that the biological processes identified through such a screen may eventually serve as novel targets for inhibition via pharmacological methods or gene therapy.