May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
Molecular Analysis of Deficits in RanBP2–Mediated Glucose Catabolism
Author Affiliations & Notes
  • M.R. Guruju
    Depts of Opthalomology, Molecular Genetics and Microbiolgy, Duke Medical Center, Durham, NC
  • P.A. Ferreira
    Depts of Opthalomology, Molecular Genetics and Microbiolgy, Duke Medical Center, Durham, NC
  • Footnotes
    Commercial Relationships  M.R. Guruju, None; P.A. Ferreira, None.
  • Footnotes
    Support  NIH Grants EY11993 ,EY12655 and RPB foundation
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 5519. doi:
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      M.R. Guruju, P.A. Ferreira; Molecular Analysis of Deficits in RanBP2–Mediated Glucose Catabolism . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5519.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : The Ran–binding protein 2 (RanBP2) is a large mosaic protein and it has been reported to exhibit a pleiotropic function. Structure–function analysis studies in our laboratory on RanBP2 found that the leucine–rich domain (LD) of RanBP2 interact with hexokinase type I (HKI) and Cox11. HKI catalyzes the rate–limiting step of glycolysis and Cox11 is a metalochaperone implicated in cytochrome c assembly. We have found that in vitro Cox 11 profoundly inhibits HKI activity and the LD of RanBP2 suppresses this inhibitory activity. In addition, haploinsufficient and inbred RanBP2 mice exhibit deficits in glucose catabolism and suppression of ERG responses without apparent impairment of other functions allied and reported to RanBP2. The focus of this study was to determine the molecular and neuronal basis of the role of RanBP2 in glucose catabolism and complications allied to hyperglycemia and retina physiology.

Methods: : We employed RanBP2+/– mice to probe the gene dosage–dependent effects of RanBP2 in the levels of HKI and intracellular concentrations of glucose and ATP. In addition, we carried–out cell culture–based assays with retinal and non–neuronal lines to examine further the effects of the LD of RanBP2 in mitochondria localization and function.

Results: : Haploinsufficiency of RanBP2 leads to a reduction of HKI protein levels in the retina, hippocampus and brain, but not other tissues tested. The reduction in HKI levels is accompanied by a decrease of ATP levels in the same tissues. Ectopic expression of the LD of RanBP2 in ganglion and photoreceptor–derived cell lines leads to strong perinuclear clustering of the mitochondria without affecting HKI distribution. Moreover, severe neuronal atrophy ensues. This phenotype seems specific for neuronal cell lines.

Conclusions: : Deficits in RanBP2 underlie a reduction of HKI and ATP levels and the latter may be a major contributing factor for modulating the Na+, K+–ATPase pump activity in neurons and thus, the suppression of the ERGs responses in RanBP2+/– mice. Moreover, ectopic expression of LD of RanBP2 uncouples the colocalization of HKI from the mitochondria, prevents its dispersion and leads ultimately to severe neuronal atrophy. Altogether, the data support the LD of RanBP2 exerts a strong modulatory and vital role on mitochondria and HKI localization and function

Keywords: genetics • metabolism • diabetes 

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