A model of the mitochondrial basis of bipolar disorder

Gerwyn Morris, Ken Walder, Sean L. McGee, Olivia M. Dean, Susannah J Tye, Michael Maes, Michael Berk

Research output: Contribution to journalReview article

26 Citations (Scopus)

Abstract

Background 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. Discussion 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. Summary 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.

Original languageEnglish (US)
Pages (from-to)1-20
Number of pages20
JournalNeuroscience and Biobehavioral Reviews
Volume74
DOIs
StatePublished - Mar 1 2017

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Bipolar Disorder
Adenosine Triphosphate
AMP-Activated Protein Kinases
Oxidative Phosphorylation
Uric Acid
Respiration
Oxidative Stress
Ions
Depression
Cytokines
Calcium
Glycogen Synthase Kinase 3
Brain-Derived Neurotrophic Factor
Melatonin
Mood Disorders
Phosphatidylinositol 3-Kinases
NAD
Glutamic Acid
Dopamine
Up-Regulation

Keywords

  • AMPK
  • Bcl-2
  • BDNF
  • Bipolar disorder
  • Depression
  • GSK-3
  • Inflammation
  • Mania
  • Melatonin
  • Mitochondria
  • Oxidative stress
  • p53
  • SIRT-1

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

Cite this

Morris, G., Walder, K., McGee, S. L., Dean, O. M., Tye, S. J., Maes, M., & Berk, M. (2017). A model of the mitochondrial basis of bipolar disorder. Neuroscience and Biobehavioral Reviews, 74, 1-20. https://doi.org/10.1016/j.neubiorev.2017.01.014

A model of the mitochondrial basis of bipolar disorder. / Morris, Gerwyn; Walder, Ken; McGee, Sean L.; Dean, Olivia M.; Tye, Susannah J; Maes, Michael; Berk, Michael.

In: Neuroscience and Biobehavioral Reviews, Vol. 74, 01.03.2017, p. 1-20.

Research output: Contribution to journalReview article

Morris, G, Walder, K, McGee, SL, Dean, OM, Tye, SJ, Maes, M & Berk, M 2017, 'A model of the mitochondrial basis of bipolar disorder', Neuroscience and Biobehavioral Reviews, vol. 74, pp. 1-20. https://doi.org/10.1016/j.neubiorev.2017.01.014
Morris, Gerwyn ; Walder, Ken ; McGee, Sean L. ; Dean, Olivia M. ; Tye, Susannah J ; Maes, Michael ; Berk, Michael. / A model of the mitochondrial basis of bipolar disorder. In: Neuroscience and Biobehavioral Reviews. 2017 ; Vol. 74. pp. 1-20.
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N2 - Background 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. Discussion 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. Summary 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.

AB - Background 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. Discussion 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. Summary 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.

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KW - Oxidative stress

KW - p53

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