Regulators of mitochondrial complex I activity: A review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder
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
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Authors contributed equally to this study