Myc and Max localize primarily to the nucleus and the activity of the complex is controlled primarily by the availability of the short-lived Myc protein. By contrast, MondoA and Mlx are both stable proteins that localize to the cytoplasm. As such, their subcellular distribution, which is mediated by interactions with the nuclear export factor CRM1 and members of the 14.3.3 family, controls their nuclear function as transcriptional activators. Surprisingly, MondoA localizes to the outer mitochondrial membrane. This finding coupled with our discovery that several key glycolytic enzymes are transcriptional targets of MondoA:Mlx, suggests that MondoA:Mlx heterocomplexes sense information about intracellular energy status at the mitochondria and communicate that information to the nucleus ultimately driving adaptive changes in gene expression.