A model of the mitochondrial basis of bipolar disorder

Morris, Gerwyn, Walder, Ken, McGee, Sean L, Dean, Olivia M, Tye, Susannah J, Maes, Michael and Berk, Michael 2017, A model of the mitochondrial basis of bipolar disorder, Neuroscience and biobehavioral reviews, vol. 74, no. Part A, pp. 1-20, doi: 10.1016/j.neubiorev.2017.01.014.

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Title A model of the mitochondrial basis of bipolar disorder
Author(s) Morris, Gerwyn
Walder, KenORCID iD for Walder, Ken orcid.org/0000-0002-6758-4763
McGee, Sean LORCID iD for McGee, Sean L orcid.org/0000-0001-6953-106X
Dean, Olivia MORCID iD for Dean, Olivia M orcid.org/0000-0002-2776-3935
Tye, Susannah J
Maes, Michael
Berk, MichaelORCID iD for Berk, Michael orcid.org/0000-0002-5554-6946
Journal name Neuroscience and biobehavioral reviews
Volume number 74
Issue number Part A
Start page 1
End page 20
Total pages 20
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2017-03
ISSN 0149-7634
Keyword(s) AMPK
Bipolar disorder
Oxidative stress
Science & Technology
Life Sciences & Biomedicine
Behavioral Sciences
Neurosciences & Neurology
Activated protein-kinase
Uric-acid levels
Dorsolateral prefrontal cortex
Glycogen-synthase kinase-3
Allosteric ATP-inhibition
Experimental allergic encephalomyelitis
Permeability transition pore
Summary 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-FO elements 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.
Language eng
DOI 10.1016/j.neubiorev.2017.01.014
Field of Research 110319 Psychiatry (incl Psychotherapy)
11 Medical And Health Sciences
17 Psychology And Cognitive Sciences
Socio Economic Objective 920410 Mental Health
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, Elsevier Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30091204

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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