The Ran-binding protein 2 (RanBP2) is a large protein with several domains. Although several protein partners were found to interact with selective domains of RanBP2, none to this date were found toward its large leucine-rich domain (LD). Cell-based experiments support several roles of RanBP2 in cell function, such as the production of functional proteins, control of protein trafficking between the nuclear and cytosol compartments, and control of multiple facets underlying cell division. Still, the genetic and physiological implications of the interactions between RanBP2 and its partners and of the function of RanBP2 in a whole-animal model remain elusive. The authors report the identification of two novel mitochondrial partners of the LD of RanBP2, Cox11 and hexokinase type I (HKI); and with multidisciplinary approaches probe the role of RanBP2 and its LD on Cox11, HKI, and functions allied to these. The authors found that RanBP2 exhibits chaperone activity toward HKI and Cox11. RanBP2 and Cox11 profoundly modulate HKI activity. Moreover, partial loss-of-function of RanBP2 in a mouse model induces deficits in growth rates and breakdown of glucose, promotes the down-regulation of HKI and ATP levels selectively in the central nervous system, and impairs visual function. These findings support a critical role of RanBP2 and its partners in metabolic processes and allied disease states.