Elsevier

Psychiatry Research

Volume 236, 28 February 2016, Pages 148-157
Psychiatry Research

Regulators of mitochondrial complex I activity: A review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

https://doi.org/10.1016/j.psychres.2015.12.015Get rights and content

Highlights

  • PARK-7, STAT3, SIRT-3, and IMP-2 play an important role in regulating complex I activity.

  • Published microarray data revealed trend towards downregulation of PARK-7 in patients with BD.

  • Immunocontent of DJ-1 was not increased in post-mortem prefrontal cortex from patients with BD.

Abstract

Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.

Section snippets

Overview of the literature

Bipolar disorder (BD) is a mood disorder associated with chronic course alternating between mania and depression, with symptoms characterized by alternating increases and decreases in energy and activity (Malhi et al., 2015). It is currently one of the main focuses of psychiatry research effort (Anderson et al., 2012). The World Health Organization (WHO) identifies BD as among the top ten leading cause of lifelong disability worldwide accounting for approximately 1–2% of the population affected

Post-mortem brain samples of microarray data

We used published microarray data from two post-mortem brain collections of the Stanley Medical Research Institute (SMRI) Online Genomic database where independent studies were conducted (https://www.stanleygenomics.org).

The first collection was from the Stanley Neuropathology Consortium, which includes brain tissue samples from various regions of the brain. The consortium collection contained brain samples from 60 subjects divided into four cases, 15 individuals each with BD, schizophrenia,

Cross-study analysis revealed trend towards downregulation of PARK-7 in BD

We combined gene expression profiles of candidate complex I regulators that may be associated with decreased complex I activity in BD. Particularly, we evaluated the expression profile of complex I regulators (PARK-7, STAT3, SIRT-3, IMP-2) in BD using large fold change magnitudes and a non-stringent p-value (p<0.05). Among the set of genes, we identified one gene that was almost consistently downregulated across multiple independent studies (Fig. 2A). When the analysis was segregated based on

Discussion

BD is a very complex illness with genetics being a significant contributing factor. However, no single gene has been consistently identified, making it challenging to come into a general consensus. Exploring gene expression may help uncover genes that are up- or downregulated in BD and thereby provide molecular insight on its genetic foundation that can help explain molecular and regulatory mechanisms in a pathway involved in the pathophysiology of BD. Gene expression studies of the prefrontal

Conclusion

To conclude, our hypothesis of the presence of altered complex I regulators based on the literature search was not supported by the microarray studies and our immunohistochemical validation data. Among the four genes (PARK-7 STAT3, SIRT-3, and IMP2), PARK-7 showed a near consistent trend towards downregulation across individual microarray studies. However, this was not supported by our immunohistochemistry data, confirming that DJ-1 is not significantly differentially regulated in BD subjects.

Conflicts of interest

None.

Acknowledgments

We thank the Stanley Medical Research Institute (SMRI)–Online Genomics Database and Elashoff Consulting, LLC for providing access to the public available microarray data. We also thank Dr. Sabine Bahn, Dr. Tadafumi Kato, Dr. Marquis P. Vawter, Dr. Trevor Young, Dr. Seth E. Dobrin, Dr. Haiming Chen, Dr. Allen A. Fienberg, Dr. Pamela Sklar collaborators from SMRI Online Genomics Database. MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. ACA is supported by Canadian

References (122)

  • N.C. Brown et al.

    An updated meta-analysis of oxidative stress markers in bipolar disorder

    Psychiatry Res.

    (2014)
  • G. Cannino et al.

    Glucose modulates respiratory complex I activity in response to acute mitochondrial dysfunction

    J. Biol. Chem.

    (2012)
  • S.J. Chinta et al.

    Reversible inhibition of mitochondrial complex I activity following chronic dopaminergic glutathione depletion in vitro: implications for Parkinson’s disease

    Free. Radic. Biol. Med.

    (2006)
  • S.J. Chinta et al.

    Up-regulation of gamma-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson’s disease

    Free. Radic. Biol. Med.

    (2006)
  • H.B. Clay et al.

    Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

    Int. J. Dev. Neurosci.

    (2011)
  • T. Cocco et al.

    Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation

    Free. Radic. Biol. Med.

    (1999)
  • C.W. Davis et al.

    Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis

    Free. Radic. Biol. Med.

    (2010)
  • M. Elschami et al.

    Reduction of STAT3 expression induces mitochondrial dysfunction and autophagy in cardiac HL-1 cells

    Eur. J. Cell. Biol.

    (2013)
  • H. Gao et al.

    DJ-1 protects dopaminergic neurons against rotenone-induced apoptosis by enhancing ERK-dependent mitophagy

    J. Mol. Biol.

    (2012)
  • Y. Glinka et al.

    Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine

    Eur. J. Pharmacol.

    (1998)
  • Y.Y. Glinka et al.

    Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine

    Eur. J. Pharmacol.

    (1995)
  • T. Hayashi et al.

    DJ-1 binds to mitochondrial complex I and maintains its activity

    Biochem. Biophys. Res. Commun.

    (2009)
  • S.J. Heales et al.

    Impairment of brain mitochondrial function by reactive nitrogen species: the role of glutathione in dictating susceptibility

    Neurochem. Int.

    (2002)
  • M. Inden et al.

    PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson’s disease rat model

    Neurobiol. Dis.

    (2006)
  • S. Jana et al.

    Dopamine but not 3,4-dihydroxy phenylacetic acid (DOPAC) inhibits brain respiratory chain activity by autoxidation and mitochondria catalyzed oxidation to quinone products: implications in Parkinson’s disease

    Brain Res.

    (2007)
  • S. Jana et al.

    Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson’s disease

    Biochim. Biophys. Acta

    (2011)
  • N. Jha et al.

    Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease

    J. Biol. Chem.

    (2000)
  • D.P. Jones et al.

    Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses

    Free. Radic. Biol. Med.

    (2002)
  • S. Karunakaran et al.

    Constitutive expression and functional characterization of mitochondrial glutaredoxin (Grx2) in mouse and human brain

    Brain Res.

    (2007)
  • J. Kulkarni et al.

    A four week randomised control trial of adjunctive medroxyprogesterone and tamoxifen in women with mania

    Psychoneuroendocrinology

    (2014)
  • J. Kulkarni et al.

    Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia

    Psychoneuroendocrinology

    (2010)
  • H.J. Kwon et al.

    DJ-1 mediates paraquat-induced dopaminergic neuronal cell death

    Toxicol. Lett.

    (2011)
  • S.I. Liochev

    Reactive oxygen species and the free radical theory of aging

    Free. Radic. Biol. Med.

    (2013)
  • G. Liu et al.

    alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity

    Neurosci. Lett.

    (2009)
  • V. Loeb et al.

    The transgenic overexpression of alpha-synuclein and not its related pathology associates with complex I inhibition

    J. Biol. Chem.

    (2010)
  • P.I. Moreira et al.

    Tamoxifen and estradiol interact with the flavin mononucleotide site of complex I leading to mitochondrial failure

    J. Biol. Chem.

    (2006)
  • S. Moylan et al.

    Oxidative & nitrosative stress in depression: why so much stress?

    Neurosci. Biobehav. Rev.

    (2014)
  • S.J. Mullett et al.

    DJ-1 knock-down in astrocytes impairs astrocyte-mediated neuroprotection against rotenone

    Neurobiol. Dis.

    (2009)
  • J. Murray et al.

    Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry

    J. Biol. Chem.

    (2003)
  • D. Nagakubo et al.

    DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras

    Biochem. Biophys. Res. Commun.

    (1997)
  • C. Nunes et al.

    Nitric oxide and DOPAC-induced cell death: from GSH depletion to mitochondrial energy crisis

    Mol. Cell. Neurosci.

    (2011)
  • D. Phillips et al.

    Stoichiometry of STAT3 and mitochondrial proteins: Implications for the regulation of oxidative phosphorylation by protein-protein interactions

    J. Biol. Chem.

    (2010)
  • J.J. Poderoso et al.

    The regulation of mitochondrial oxygen uptake by redox reactions involving nitric oxide and ubiquinol

    J. Biol. Chem.

    (1999)
  • B.H. Ahn et al.

    A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • I.M. Anderson et al.

    Bipolar disorder

    Br. Med. J.

    (2012)
  • A.C. Andreazza et al.

    Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder

    Arch. Gen. Psychiatry

    (2010)
  • A.C. Andreazza et al.

    The neurobiology of bipolar disorder: identifying targets for specific agents and synergies for combination treatment

    Int. J. Neuropsychopharmacol.

    (2014)
  • R. Bandopadhyay et al.

    The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease

    Brain

    (2004)
  • J.S. Beckman et al.

    Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly

    Am. J. Physiol.

    (1996)
  • D. Ben-Shachar et al.

    The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons

    J. Neurochem.

    (1991)
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