title: Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons.
abstract: We tested the hypothesis that neurotrophic factors control neuronal metabolism by directly regulating mitochondrial function in the absence of effects on survival. Real-time whole cell fluorescence video microscopy was utilized to analyze mitochondrial inner membrane potential (Delta Psi(m)), which drives ATP synthesis, in cultured adult sensory neurons. These adult neurons do not require neurotrophic factors for survival. Insulin and other neurotrophic factors increased Delta Psi(m) 2-fold compared with control over a 6- to 24-h period (P < 0.05). Insulin modulated Delta Psi(m) by activation of the phosphoinositide 3-kinase (PI 3-K) pathway. Insulin also induced rapid and long-term (30 h) PI 3-K-dependent phosphorylation of Akt and cAMP response element binding protein (CREB). Additionally, insulin elevated the redox state of the mitochondrial NAD(P)H pool, increased hexokinase activity (first committed step of glycolysis), and raised ATP levels. This study demonstrates that insulin utilizes the PI 3-K/Akt pathway to augment ATP synthesis that we propose contributes to the energy requirement for neurotrophic factor-driven axon regeneration.
authors.affiliation: School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Tze-Jen
authors.initials: TJ
authors.lastname: Huang
authors.forename: Alex
authors.initials: A
authors.lastname: Verkhratsky
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
mesh_terms: D051697:Activating Transcription Factor 1; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D051697:Activating Transcription Factor 1; D000255:Adenosine Triphosphate; D004268:DNA-Binding Proteins; D006593:Hexokinase; D007328:Insulin; D009249:NADP; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C494920:Akt1 protein, rat