Our findings support that RanBP2 plays a determinant role in modulating glucose and energy homeostasis. The data support that Cox1 and HKI are novel partners in vivo for the large LD of RanBP2 (Figures 1 and 2). The LD of RanBP2 exhibits chaperone activity toward folding intermediates of Cox11, and possibly, the mature HKI (Figure 1). Cox11 inhibits noncompetitively the activity of HKI with ~2–3 molecules of Cox11 (assuming formation of Cox11 dimer) required to inhibit completely the activity of a molecule of HKI (Figure 2A and 2B). Cox11 sequesters HKI by binding to HKI at a site that is distinct from the active site and effectively reduces the availability of [HKI]tot for catalysis. This is reflected by a reduction of the V max of HKI without significantly affecting the K m of the active site of HKI toward glucose (Figure 2A and 2B). The inhibitory property of Cox11 over HKI is suppressed by RanBP2 (Figure 2C), which by itself has a weak but significant inhibitory activity over HKI (Figure 2D). The sub-stochiometry effect of the LD of RanBP2 over the inhibition of HKI by Cox11 supports that a LD-dependent chaperonin-like mechanism underlies the suppression of Cox11-dependent inhibition of HKI by RanBP2, and that RanBP2 acts as a molecular “buffer” over HK1 and Cox11 activities. The partial loss of the RanBP2 chaperone activity in RanBP2+/− mice also leads to deficits in the sequestration of HKI in the ellipsoid compartment of photosensory neurons. This possibly underlies the mistargeting of HKI to the myoid compartment of these neurons (Figure S2). The data support that the ultimate pathophysiological outcome in HKI, caused by a reduction in RanBP2 levels and its chaperone activity, is the selective degradation of HKI as reflected by the reduced levels of HKI (and ATP) but not of other mitochondrial and NPC components (Figure 5). Through this process, it is also possible that deficits in RanBP2 cause a disturbance in the equilibrium between Cox11, HK1, and RanBP2 by leading to an increase of the inhibitory activity of Cox11 over HKI that promotes the uncoupling of the interaction of HKI from RanBP2, ultimately causing HKI degradation. Regardless, lower levels of HKI likely contribute to the decreased levels in ATP, slower growth rates, and diminished ability to metabolize glucose of RanBP2+/− mice (Figures 5–7). As discussed subsequently, the ATP deficits in the retina likely account for the reduced electrophysiological responses of retinal neurons (Figure 8).