title: A model of the mitochondrial basis of bipolar disorder.
abstract: Bipolar disorder phenomenologically is a biphasic disorder of energy availability; increased in mania and decreased in depression. In consort, there is accumulating evidence indicating increased mitochondrial respiration and ATP production in bipolar mania which contrasts with decreased mitochondrial function in patients in the euthymic or depressive phase of the illness. Consequently, the central thesis of this paper is that bipolar disorder is due to a phasic dysregulation of mitochondrial biogenergetics. The elements responsible for this dysregulation may thus represent critical treatment targets for mood disorders, and are the subject of this paper.
  
  
  
  There are many potential mediators of mitochondrial function which collectively are implicated in bipolar disorder. Levels of oxidative stress, pro-inflammatory cytokines and intracellular calcium ions are all higher in bipolar mania than in the euthymic and depressive phases of the illness. Increased levels of calcium ions can partly account for increased oxidative phosphorylation via well documented pathways such as the modulation of the F1-FOelements of ATP synthase. Likewise, increased levels of oxidative stress and pro-inflammatory cytokines lead to the upregulation of AMPK, SIRT-1, SIRT-3 and NAD+which directly stimulate oxidative phosphorylation. Uric acid and melatonin are also differentially elevated in bipolar mania and both molecules stimulate the production of ATP. The pro-apoptotic, neurotoxic and mitotoxic effects of elevated glutamate, dopamine and GSK-3 in bipolar mania may be counterbalanced by higher basal levels and activity of p53, Bcl-2, PI3K and Akt in an environment of elevated uric acid and decreased BDNF.
  
  
  
  Details of these pathways are discussed as an explanatory model for the existence of increased ATP generation in mania. We also offer a model explaining the biphasic nature of mitochondrial respiration in bipolar disorder and the transition between mania and depression based on increasing levels of TNFα, ROS, NO, AMPK and SIRT-1 together with the antagonistic relationship between p53 and NF-κB.
authors.affiliation: Tir Na Nog, Bryn Road Seaside 87, Llanelli, SA152LW, Wales, United Kingdom.
authors.forename: Gerwyn
authors.initials: G
authors.lastname: Morris
authors.affiliation: Deakin University, The Centre for Molecular and Medical Research, School of Medicine, P.O. Box 291, Geelong, 3220, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.affiliation: Deakin University, The Centre for Molecular and Medical Research, School of Medicine, P.O. Box 291, Geelong, 3220, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 291, Geelong, 3220, Australia.
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Dean
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 291, Geelong, 3220, Australia; Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, United States; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, United States; Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, United States; School of Psychology, Deakin University, 221 Burwood Highway, Burwood, VIC 3154, Australia.
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Tye
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 291, Geelong, 3220, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
authors.affiliation: Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 291, Geelong, 3220, Australia; Orygen Youth Health Research Centre and the Centre of Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville, 3052, Australia. Electronic address: MIKEBE@BarwonHealth.org.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
mesh_terms: D001714:Bipolar Disorder; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D008928:Mitochondria; D019964:Mood Disorders; D019869:Phosphatidylinositol 3-Kinases
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3
keywords: AMPK; BDNF; Bcl-2; Bipolar disorder; Depression; GSK-3; Inflammation; Mania; Melatonin; Mitochondria; Oxidative stress; SIRT-1; p53