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human mitochondrial replicaseThe mitochondrion is the energy producing organelle in the cell, and the only organelle in animal cells besides the nucleus that contains its own chromosome. Maintenance of mitochondrial function requires the replication and expression of the mitochondrial genome. Remarkably, not a single gene involved in mitochondrial molecular biology is encoded in the compact mitochondrial genome: all of the protein machinery for replication, transcription, and translation (and DNA repair functions) is encoded in the nucleus, and the relevant proteins must be imported into the mitochondrion.

Our research is centered around understanding the molecular mechanisms involved in the replication and expression of the mitochondrial DNA genome and their regulation. Our experimental approach is to employ a combination of biochemical and molecular genetic methods toward the development of in vitro and transgenic systems from Drosophila. Efforts are focused in two major areas. The first is structure-function analysis of nuclear-encoded proteins involved in mitochondrial function. These currently include: the mitochondrial DNA polymerase that was purified and cloned for the first time in our laboratory, mitochondrial single-stranded DNA-binding protein (mtSSB), mtDNA helicase, mtDNA sequence-specific binding proteins involved in regulation of replication and transcription, protein components of the mitochondrial chromosome, and mtRNA polymerase.

A second research effort is on elucidation of the organization, structure and regulated expression of the nuclear genes encoding mitochondrial proteins and in particular, those involved in mitochondrial molecular biology. Currently under study are the genes encoding the two subunits of mitochondrial DNA polymerase and those for mtDNA helicase and mtSSB, and the nuclear proteins that regulate their expression.

Studies of mitochondrial molecular biology and evolution are crucial to our understanding of mitochondrial biogenesis and its relationship to cell growth and its regulation. The expanding repertoire of mitochondrial diseases emphasizes the need for future research on the structure and fidelity of the mitochondrial replication apparatus and on nuclear-mitochondrial interactions in the regulation of mitochondrial DNA transactions.