Dual Genome Omics: Adapting Genomics Techniques to Reveal Molecular Pathology in Mitochondrial Disease

PROJECT SUMMARY Mitochondrial disorders are rare, often devastating genetic diseases affecting the brain, muscle, and other organs caused by genetic failure of mitochondria, cellular structures that produce most of the cell’s energy. Critically, there are no proven lab tests to track mitochondrial disease progression and no FDA-approved therapies. Many hurdles exist to studying mitochondrial disorders in order to change this, two of which we address in this project. First, because they are often most severely affected, earlier studies of mitochondrial disease have focused on patient biopsy samples such as skeletal muscle that require surgery to obtain. Based on clinical and research data, we are using blood instead, allowing us to collect many more samples without painful and expensive procedures. Second, two sets of genes—nuclear and mitochondrial—are needed to make mitochondria; and most methods used to study genes and their functional status can only be used to examine one type. We are using modified techniques to allow us to study the presence of damaged mitochondrial genes and functional status of nuclear genes at the same time. Using these two new approaches, we have discovered a new cell type-specific pattern of damaged mitochondrial genes. In this proposal, we aim to determine if cell type-specific patterns of damaged mitochondrial genes track with disease progression, how these patterns arise, and how the amount of damaged mitochondrial genes related to mitochondrial function in single cells. If successful, these experiments will improve our understanding of how genetic changes cause the symptoms of mitochondrial disease and may lead to theories of how to develop clinical lab tests for mitochondrial disease severity and, potentially, theories of how to treat mitochondrial disorders.