title: 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.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Dean A. McGee Eye Institute, Oklahoma City, OK 73104, USA.
authors.forename: Ammaji
authors.initials: A
authors.lastname: Rajala
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Gupta
authors.forename: Robert E
authors.initials: RE
authors.lastname: Anderson
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008027:Light; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000091402:Prohibitins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism / Q000528:radiation effects*; D012160:Retina / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006593:Hexokinase; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000091402:Prohibitins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; C000717328:PHB protein, human; C000605506:GSK3B protein, human; C000605508:Gsk3b protein, rat; C553451:PHLPP1 protein, rat
keywords: GSK-3β; Glycogen synthase kinase; HK-II; HSP60; Hexokinase; IR; Insulin receptor; Mitochondria; Neuroprotection; PH domain and leucine-rich repeat protein phosphatase-like; PHB1; PHLPPL; PI3K; Phosphoinositide 3-kinase; ROS; VDAC; glycogen synthase kinase-3β; heat shock protein 60; hexokinase; insulin receptor; phosphoinositide 3-kinase; prohibitin-1; rod outer segments; voltage-dependent anion channel