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.
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.
© 2013.