Mitochondria are organelles that provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ) and bipolar disorder (BD). The overarching hypothesis for this grant is that mitochondrial dysfunction is one of the risk factors for SZ and BD based upon evidence of mitochondrial dysfunction in transcriptomic, proteomic, and metabolomic studies, genetic studies of families, in vivo neuroimaging studies, and mitochondrial DNA (mtDNA) sequence variations. Several mildly deleterious mutations in mtDNA have been reported in SZ and BD patients. The investigators found deletion of a large portion of mtDNA was increased in the brain, dorsolateral prefrontal cortex (DLPFC), of BD subjects relative to age-matched controls. The substitution of synonymous base pairs in the entire mtDNA genome was elevated in DLPFC of individuals with SZ compared to controls and subjects with SZ had a significantly decreased expression of 10 mtDNA transcripts. The decreased expression of mtDNA transcripts in SZ might be related to increased mtDNA substitution in the control or coding regions which will be tested. The causes for increased base pair substitutions in SZ might be inherited or accumulated substitutions in brain. Two of the aims for this grant are to study mtDNA substitutions in brain and to compare the substitution rate in the same subjects9 germ line tissue. This grant proposes to examine mtDNA common deletion, copy number, and transcript abundances in brain from individuals with SZ and BD and compare to controls. The accumulation of novel mtDNA substitutions and deletions in brain might be a risk factor for BD and SZ, and has a great potential significance in determining future targets for therapy of chronic mood and psychotic disorders. This study fills a void as there has not been an integrative brain study of the entire mitochondrial genome and transcriptome conducted in the same subjects with psychiatric disorders. A comprehensive integration of data from the genome and transcriptome of brain mitochondria can show whether moderate dysfunction in one or both systems leads to disease threshold. Focusing on the mitochondria, as a target organelle of functional brain deficits, may lead to improvements in integrative treatments that improve mitochondrial health and brain function.

Public Health Relevance

Project Narrative/Relevance The causes of schizophrenia and bipolar disorder have not been discovered. This grant proposes to analyze mitochondrial DNA, contained in brain cells, which might harbor abnormal structure and sequence. Alterations in mitochondrial sequence during the lifespan in brain might contribute to risk of developing a serious mental disorder. By understanding the accumulation of mitochondrial DNA defects in brain, it will advance mitochondrial medicine for earlier diagnosis and treatment of brain related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085801-04
Application #
8241152
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Meinecke, Douglas L
Project Start
2009-07-01
Project End
2014-01-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$378,675
Indirect Cost
$131,175
Name
University of California Irvine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Mamdani, Firoza; Rollins, Brandi; Morgan, Ling et al. (2014) The somatic common deletion in mitochondrial DNA is decreased in schizophrenia. Schizophr Res 159:370-5
Guella, Ilaria; Sequeira, Adolfo; Rollins, Brandi et al. (2014) Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex. Schizophr Res 152:111-6
Kenney, M Cristina; Chwa, Marilyn; Atilano, Shari R et al. (2014) Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases. Biochim Biophys Acta 1842:208-19
van Erp, Theo G M; Guella, Ilaria; Vawter, Marquis P et al. (2014) Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation. Biol Psychiatry 75:398-405
Nurnberger Jr, John I; Koller, Daniel L; Jung, Jeesun et al. (2014) Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry 71:657-64
Mamdani, Firoza; Martin, Maureen V; Lencz, Todd et al. (2013) Coding and noncoding gene expression biomarkers in mood disorders and schizophrenia. Dis Markers 35:11-21
Guella, Ilaria; Sequeira, Adolfo; Rollins, Brandi et al. (2013) Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. J Psychiatr Res 47:1215-21
Sequeira, P Adolfo; Martin, Maureen V; Vawter, Marquis P (2012) The first decade and beyond of transcriptional profiling in schizophrenia. Neurobiol Dis 45:23-36
Lee, Candy S; Lee, Chiashan; Hu, Terry et al. (2011) Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration. Proc Natl Acad Sci U S A 108:8408-13
Vawter, Marquis P; Mamdani, Firoza; Macciardi, Fabio (2011) An integrative functional genomics approach for discovering biomarkers in schizophrenia. Brief Funct Genomics 10:387-99

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