Light activation of the insulin receptor regulates mitochondrial hexokinase. A possible mechanism of retinal neuroprotection.

Abstract

The serine/threonine kinase Akt has been shown to mediate the anti-apoptotic activity through hexokinase (HK)-mitochondria interaction. We previously reported that Akt activation in retinal rod photoreceptor cells is mediated through the light-dependent insulin receptor (IR)/PI3K pathway. Our data indicate that light-induced activation of IR/PI3K/Akt results in the translocation of HK-II to mitochondria. We also found that PHLPPL, a serine/threonine phosphatase, enhanced the binding of HK-II to mitochondria. We found a mitochondrial targeting signal in PHLPPL and our study suggests that Akt translocation to mitochondria could be mediated through PHLPPL. Our results suggest that the light-dependent IR/PI3K/Akt pathway regulates hexokinase-mitochondria interaction in photoreceptors. Down-regulation of IR signaling has been associated with ocular diseases of retinitis pigmentosa, diabetic retinopathy, and Leber Congenital Amaurosis-type 2, and agents that enhance the binding interaction between hexokinase and mitochondria may have therapeutic potential against these ocular diseases.

• Authors: Ammaji Rajala, Vivek K Gupta, Robert E Anderson, Raju V S Rajala
• Journal: Mitochondrion (Mitochondrion) Vol. 13 Issue 6 Pg. 566-76 (Nov 2013) ISSN: 1872-8278 [Electronic] Netherlands
• PMID: 23993956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• DNA Primers
• Nuclear Proteins
• PHB protein, human
• Prohibitins
• Hexokinase
• Receptor, Insulin
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• PHLPP1 protein, rat

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• DNA Primers
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• HEK293 Cells
• Hexokinase (metabolism)
• Humans
• Light
• Mitochondria (enzymology)
• Molecular Sequence Data
• Nuclear Proteins (chemistry, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prohibitins
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, Insulin (metabolism, radiation effects)
• Retina (enzymology, metabolism, radiation effects)
• Signal Transduction