The Role of Stat1 in Mitochondria

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DESCRIPTION (provided by applicant): The Stat family of transcription factors are well known to control the expression of nuclear encoded cellular genes. As a consequence of incubation of cells with a variety of cytokines and growth factors the Stats are activated by tyrosine phosphorylation resulting in their nuclear translocation. Previous studies have reported that the expression of several mitochondria encoded RNAs is inhibited as a result of incubation of cells with type one interferons (IFN alpha/beta). Preliminary data presented in this application indicates that Stat1 is constitutively present in the mitochondria of both human and mouse cells. In primary murine pro B cells and MEFs isolated from Stat1-null mice the expression of all RNAs that encode mitochondria synthesized proteins are elevated 3 to 8 fold compared to pro B cells or MEFs derived from wild type littermates. Furthermore, we are able to demonstrate that Stat1 binds to the D-loop region of the mitochondrial genome where transcription of the mitochondrially encoded genes is initiated. We hypothesize that Stat1 plays an important role in the expression of mitochondrial encoded mRNAs and possibly other functions involved in electron transport. To test this hypothesis we will perform the following specific aims: 1) Determine whether decreased expression of mitochondria-encoded RNAs is mediated by Stat1 localized in the mitochondria and identify the domains in Stat1 required for its localization in the mitochondria. 2) Determine whether viral infection or IFN beta treatment of cells alters expression of mitochondria-encoded mRNAs and mitochondria respiration.