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Eric Shoubridge’s laboratory focuses on the molecular genetics of mitochondrial diseases, in particular, those that affect the function of the respiratory chain. Mitochondria are essential for a number of cellular processes such as heme and iron-sulfur cluster biosynthesis, and for aerobic energy production. Energy production occurs in the respiratory chain, a system composed of five multi-subunit enzyme complexes whose polypeptide components are encoded in both the nuclear and mitochondrial genomes (mtDNA). Although only a handful of polypeptides are encoded in mtDNA, all are essential. Defects in respiratory chain function have been linked to a wide spectrum of multi-system disorders, often referred to as encephalomyopathies because of the prominent involvement of the nervous system and skeletal muscle. These defects have an estimated prevalence of one in every five thousand births. Defects can be caused by mutations in nuclear genes or in mtDNA.

The genetics of mtDNA is completely different from Mendelian genetics because of the high ploidy of mtDNA and because it is inherited maternally. Most cells contain hundreds or thousands of copies of mtDNA. In patients with mitochondrial disease, pathogenic mtDNAs usually co-exist with wild-type mtDNAs (heteroplasmy). In general, the proportion of mutant mtDNAs must exceed a particular threshold to produce a biochemical phenotype, so the rules that govern the transmission of mtDNA in the female germline, and the segregation of mutant mtDNAs in different tissues during fetal and postnatal life, are important determinants of the expression of a pathogenic phenotype, specific tissue involvement, and the severity of disease. The factors affecting the transmission and segregation of pathogenic mtDNA mutants remain, however, poorly understood. Using biochemical and genetic approaches, we are investigating the structural organization of mtDNA, and the nature of the nuclear genetic factors that influence its transmission and segregation.

Most nuclear genetic effects affecting respiratory chain function are inherited as autosomal recessive traits. These are most prevalent in the pediatric population, where they are associated with severe respiratory chain dysfunction and an early fatal outcome. Using functional complementation cloning techniques in cell lines from patients, we are identifying and characterizing the genes associated with these disorders. The vast majority of these deficiencies result from an inability to assemble one or more of the respiratory chain complexes. This has led us to investigate the pathways of assembly of the individual enzyme complexes as well as the mitochondrial translation system that synthesizes the essential structural components encoded in mtDNA.