The mitochondrion is the center stage for energy metabolism, apoptosis, signaling, and ion homeostasis. Much of what we know about this organelle comes from studying genetic disorders of the organelle. These are devastating disorders that are due to genetic defects in the mtDNA or the nuclear DNA that give rise to a malfunctioning mitochondrial respiratory chain, the core machinery for oxidative phosphorylation (OXPHOS). Virtually all organ systems can be affected. OXPHOS disease affects an estimated 1:5000 live births and is devastating - it is extremely difficult to diagnose, requiring consultation by multiple physicians and invasive biopsies, and at present, and no effective therapies are available. A small fraction of mitochondrial OXPHOS disorders are maternally inherited, but the vast majority are due to mutations in nuclear genes, many of which have yet to be identified. Our research team has recently used integrated proteomics to define the ~1100 nuclear genes that encode the mitochondrial proteome - these genes represent a near-comprehensive collection of candidate genes for OXPHOS disease. We are now applying next-generation sequencing technology to sequence all ~1100 nuclear genes in a panel of over 100 patients with clinical evidence of OXPHOS disease. In the proposed project, we plan to (1) begin with the gene variants we discover through medical next-generation sequencing and perform cDNA rescue studies to create an experimentally validated catalog of mitochondrial OXPHOS disease genes and then (2) assign novel, validated disease genes to specific steps in the mitochondrial pathway for OXPHOS biogenesis. Our work will capitalize on the rich set of new variants we are discovering through ARRA funded next generation medical sequencing. If successful, our work will improve our ability to establish molecular diagnoses in these crippling disorders. The genes and pathways we discover may shed insights into the pathogenesis of some very common diseases, such as neurodegeneration, diabetes, and infantile mortality, which may stem from dysfunction in this organelle. Finally, this project promises to have a valuable impact in fundamental biochemistry by revealing new proteins required for the assembly and biogenesis of the OXPHOS system.

Public Health Relevance

The mitochondrial OXPHOS diseases collectively represent the most common inborn error of metabolism. The prevalence is estimated to be 1:5000 live births. These disorders can present in childhood or in young adulthood and are difficult to diagnose and manage, and no cures are available. The proposed project aims to help establish a validated collection of genes that underlie these disorders. The results will aid in the diagnosis and management of these devastating disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Krasnewich, Donna M
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Massachusetts General Hospital
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