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Mitochondrial proteins encoded by nuclear DNA, which interact either with mitochondrial DNA (mtDNA) or with mitochondrial gene products, can cause defects in mtDNA maintenance. We and others have identified mutations in three different genes underlying dominantly inherited progressive external ophthalmoplegia (AdPEO) with multiple mtDNA deletions. These genes are mitochondrial DNA polymerase (POLG), the mitochondrial adenine nucleotide transporter (ANT1), and a DNA helicase named Twinkle. In addition, patients with tissue specific mtDNA depletion (that is mtDNA depletion syndrome, or MDS) may have mutations in thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK). MDS is a disorder with a devastatingly severe phenotype, which demonstrates that nucleo-mitochondrial interactions are central to normal cell function. Yet very little is known about such interactions in cells from either normal or diseased individuals. At present mtDNA diseases are incurable although the symptoms can be treated. Prenatal diagnosis is rarely available. We are studying the basic science underlying defects of mtDNA maintenance and elucidating the effects of mutants on mtDNA replication, nucleoid structure, and cell function.

This work will have implications for other types of mtDNA disease such as diseases of old age, like type 2 diabetes. Understanding the interactions between such mtDNA variants and the nuclear proteins involved in mtDNA replication will pave the way to rational therapies.