Novel Complex Interactions Between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Overview

Journal Mol Neuropsychiatry

Specialty Psychiatry

Date 2019 Apr 26

PMID 31019915

Citations 18

Authors

Anton Schulmann

Euijung Ryu

Vanessa Goncalves

Brandi Rollins

Michael Christiansen

Mark A Frye

Joanna Biernacka

Marquis P Vawter

Affiliations

Soon will be listed here.

Abstract

Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ ( = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

Citing Articles

Ketogenic Diet as a Nutritional Metabolic Intervention for Obsessive-Compulsive Disorder: A Narrative Review.

Lounici A, Iacob A, Hongler K, Molling M, Drechsler M, Hersberger L Nutrients. 2025; 17(1.

PMID: 39796465 PMC: 11723184. DOI: 10.3390/nu17010031.

Calcium Signaling and Molecular Adhesion Processes May Hold the Key to Genetic Risk for Autism: A Molecular Pathway Analysis on Two Independent Samples.

Drago A, Calabro M, Crisafulli C Genes (Basel). 2025; 15(12.

PMID: 39766876 PMC: 11675254. DOI: 10.3390/genes15121609.

Research progress in mitochondrial quality control in schizophrenia.

Chu H, Cui C, Su X, Zhang H, Ma J, Zhu H Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024; 49(1):128-134.

PMID: 38615174 PMC: 11017019. DOI: 10.11817/j.issn.1672-7347.2024.230398.

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.

Tripathi K, Ben-Shachar D Cells. 2024; 13(5.

PMID: 38474374 PMC: 10930936. DOI: 10.3390/cells13050410.

Identification of eight genomic protective alleles for mitochondrial diabetes by Kinship-graph convolutional network.

Wang J, Yan D, Cui H, Zhang R, Ma X, Chen L J Diabetes Investig. 2023; 15(1):52-62.

PMID: 38157301 PMC: 10759726. DOI: 10.1111/jdi.14125.

References

Szatkiewicz J, ODushlaine C, Chen G, Chambert K, Moran J, Neale B . Copy number variation in schizophrenia in Sweden. Mol Psychiatry. 2014; 19(7):762-73. PMC: 4271733. DOI: 10.1038/mp.2014.40. View

Nachman M, Brown W, Stoneking M, Aquadro C . Nonneutral mitochondrial DNA variation in humans and chimpanzees. Genetics. 1996; 142(3):953-63. PMC: 1207032. DOI: 10.1093/genetics/142.3.953. View

Konradi C, Eaton M, MacDonald M, Walsh J, Benes F, Heckers S . Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004; 61(3):300-8. DOI: 10.1001/archpsyc.61.3.300. View

Mosquera-Miguel A, Torrell H, Abasolo N, Arrojo M, Paz E, Ramos-Rios R . No evidence that major mtDNA European haplogroups confer risk to schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2012; 159B(4):414-21. DOI: 10.1002/ajmg.b.32044. View

Ben-Shachar D, Zuk R, Gazawi H, Reshef A, Sheinkman A, Klein E . Increased mitochondrial complex I activity in platelets of schizophrenic patients. Int J Neuropsychopharmacol. 2001; 2(4):245-253. DOI: 10.1017/S1461145799001649. View

Craddock N, ODonovan M, Owen M . The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet. 2005; 42(3):193-204. PMC: 1736023. DOI: 10.1136/jmg.2005.030718. View

Naydenov A, MacDonald M, Ongur D, Konradi C . Differences in lymphocyte electron transport gene expression levels between subjects with bipolar disorder and normal controls in response to glucose deprivation stress. Arch Gen Psychiatry. 2007; 64(5):555-64. DOI: 10.1001/archpsyc.64.5.555. View

Park C, Park S . Molecular links between mitochondrial dysfunctions and schizophrenia. Mol Cells. 2012; 33(2):105-10. PMC: 3887718. DOI: 10.1007/s10059-012-2284-3. View

Kenney M, Chwa M, Atilano S, Falatoonzadeh P, Ramirez C, Malik D . Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions. Hum Mol Genet. 2014; 23(13):3537-51. PMC: 4049308. DOI: 10.1093/hmg/ddu065. View

10.

Li X, Zhang W, Tang J, Tan L, Luo X, Chen X . Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations?. Sci Rep. 2015; 5:11076. PMC: 4459149. DOI: 10.1038/srep11076. View

11.

Mantel N, Haenszel W . Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959; 22(4):719-48. View

12.

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

13.

Kato T, Kato N . Mitochondrial dysfunction in bipolar disorder. Bipolar Disord. 2001; 2(3 Pt 1):180-90. DOI: 10.1034/j.1399-5618.2000.020305.x. View

14.

Mertens J, Wang Q, Kim Y, Yu D, Pham S, Yang B . Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015; 527(7576):95-9. PMC: 4742055. DOI: 10.1038/nature15526. View

15.

Fromer M, Pocklington A, Kavanagh D, Williams H, Dwyer S, Gormley P . De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014; 506(7487):179-84. PMC: 4237002. DOI: 10.1038/nature12929. View

16.

Altar C, Jurata L, Charles V, Lemire A, Liu P, Bukhman Y . Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry. 2005; 58(2):85-96. DOI: 10.1016/j.biopsych.2005.03.031. View

17.

Arion D, Corradi J, Tang S, Datta D, Boothe F, He A . Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry. 2015; 20(11):1397-405. PMC: 4492919. DOI: 10.1038/mp.2014.171. View

18.

Ryu E, Nassan M, Jenkins G, Armasu S, Andreazza A, McElroy S . A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation. Mol Neuropsychiatry. 2018; 3(3):125-134. PMC: 5836158. DOI: 10.1159/000464444. View

19.

Sheng Z . Mitochondrial trafficking and anchoring in neurons: New insight and implications. J Cell Biol. 2014; 204(7):1087-98. PMC: 3971748. DOI: 10.1083/jcb.201312123. View

20.

Euesden J, Lewis C, OReilly P . PRSice: Polygenic Risk Score software. Bioinformatics. 2015; 31(9):1466-8. PMC: 4410663. DOI: 10.1093/bioinformatics/btu848. View