Regulation of mitochondrial function by the members of Jak/Stat family

Members of the Jak/Stat signaling pathway play an important role in various cytokine-mediated biological responses such as regulation of cell growth and modulation of immune responses. Under unstimulated conditions, members of Jak family of kinases are usually found associated with the cytokine receptors present on the plasma membrane. Jak kinases are activated when ligands bind their specific receptor resulting tyrosine phosphorylation of latent cytoplasmic transcription factors termed as signal transducers and activators of transcription (Stats). Activated Stats will then translocate to the nucleus and drive expression of specific genes that are associated with a given biological response.; The antigrowth properties of Interferons (IFNs) are particularly important in the treatment of a number of hematopoietic as well as non-hematopoietic malignancies. The antiproliferative actions of IFNalpha/beta are variable and are largely cell-type specific. For example, incubation of primary murine pro-B cells with IFNalpha/beta induces apoptosis in these cells. Though the mechanisms are not very clear, the apoptotic actions of IFNalpha/beta are often associated with changes in mitochondrial function. However, the precise involvement of Jak/Stat family proteins in the regulation of mitochondrial function by IFNalpha/beta in these cells is not clear.; We report here for the first time that several members of the Stat family of transcription factors, including Stat1 and Stat3 but not Stat2, are present in the mitochondria of a number of cultured cells and tissues, in addition to their well known localization in the cytoplasm. Our results show that mitochondrial Stat1 constitutively associates with the mitochondrial D-loop regulatory region in primary murine pro-B cells and appears to negatively regulate the expression of mitochondrial-encoded mRNAs. Interestingly, expression of Stat3, another member of Stat family, is required for maintaining mitochondrial respiration and steady state ATP concentrations in these cells. Our results further indicate that expression of the Tyk2 kinase is also required for the integrity of mitochondrial electron transport chain and IFNbeta-induction of apoptosis in primary murine pro-B cells. All together, our results provide a novel role of Jak/Stat family members in regulating mitochondrial mRNA expression and function.