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The hepatitis B virus X protein (HBx) plays essential roles in viral replication and the generation of hepatocellular carcinoma. In spite of a large number of suggestive cellular targets and functions, a clear picture of its mechanism(s) of action has remained elusive. In this report, we continue to characterize its recently described mitochondrial association and further examine its impact on mitochondrial functions. HBx was previously shown to bind to a voltage-dependent anion channel (VDAC3) and alter the mitochondrial transmembrane potential (ΔΨ_m). Here we show that, as a consequence of association with mitochondria, HBx constitutively induces activation of transcription factors, which include STAT-3 and NF-κB. This induction of activation was sensitive to the antioxidantsN-acetyl l-cysteine and pyrrolidine dithiocarbamate, as well as to overexpression of Mn-superoxide dismutase. These results therefore …