Mitochondrial DNA (mtDNA) and schizophrenia

Verge, Begoña; Alonso, Yolanda; Valero, Joaquı́n; Miralles, Carmen; Vilella, Elisabet; Martorell, Lourdes

doi:10.1016/j.eurpsy.2010.08.008

Cited by 80 publications

(67 citation statements)

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“…Briefly, mitochondrial dysfunction, maternal inheritance, and the comorbidity of schizophrenia and mitochondrial disorders related to mtDNA mutations have been reported [Verge et al, 2011;Anglin et al, 2012]. It is worth noting that alterations in mitochondria and in mtDNA have been found in schizophrenia.…”

Section: Mtdna and Schizophreniamentioning

confidence: 98%

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia

Torrell

Salas

Abasolo

et al. 2014

American J of Med Genetics Pt B

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It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia.

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Section: Mtdna and Schizophreniamentioning

confidence: 98%

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia

Torrell

Salas

Abasolo

et al. 2014

American J of Med Genetics Pt B

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“…Evidence of mitochondrial dysfunction in schizophrenia includes genetic (Marchbanks et al, 2003; Kvajo et al, 2008; Verge et al, 2011), metabolic (Prabakaran et al, 2004), enzymatic (Prince et al, 1999, 2000; Maurer et al, 2001) and anatomical abnormalities (reviewed herein). The production of ATP and calcium buffering are essential in maintaining synaptic strength and abnormalities in these processes could lead to decreased metabolism and defective synaptic activity (Ben-Shachar and Laifenfeld, 2004; Chang and Reynolds, 2006; Duchen et al, 2008).…”

Section: Mitochondrial Abnormalities In Schizophreniamentioning

confidence: 99%

Postmortem studies on mitochondria in schizophrenia

Roberts

2017

Schizophrenia Research

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The aim of this paper is to provide a brief review of mitochondrial structure as it relates to function and then present abnormalities in mitochondria in postmortem schizophrenia with a focus on ultrastructure. Function, morphology, fusion, fission, motility, ΔΨmem, ATP production, mitochondrial derived vesicles, and mitochondria-associated ER membranes will be briefly covered. Pathology in mitochondria has long been implicated in schizophrenia, as shown by genetic, proteomic, enzymatic and anatomical abnormalities. The cortex and basal ganglia will be reviewed. In the anterior cingulate cortex, the number of mitochondria per neuronal somata in layers 5/6 in schizophrenia is decreased by 43%. There are also fewer mitochondria in terminals forming axospinous synapses. In the caudate and putamen the number of mitochondria is abnormal in both glial cells and neurons in schizophrenia subjects, the extent of which depends on treatment, response and predominant lifetime symptoms. Treatment-responsive schizophrenia subjects had about a 40% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen, while treatment resistant cases had normal values. A decrease in mitochondrial density in the neuropil distinguishes paranoid from undifferentiated schizophrenia. The appearance, size and density of mitochondria were normal in the nucleus accumbens. In the substantia nigra, COX subunits were affected in rostral regions. Mitochondrial hyperplasia occurs within axon terminals that synapse onto dopamine neurons, but mitochondria in dopamine neuronal somata are similar in size and number. In schizophrenia, mitochondria are differentially affected depending on the brain region, cell type, subcellular location, treatment status, treatment response and symptoms.

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“…However, it does not per se refute the mitochondrial pathogenic paradigm 34 where variation in mitochondrial function, believed to interfere with ATP production 35,36 , inflammation and signaling 37,38 as well as Ca 2+ -homeostasis 39 , and apoptosis 38 , is considered to be of paramount importance for development of disease. Several neuroanatomical postmortem findings in SZ brains indicate perturbed mitochondrial function 40 , but such findings are difficult to distinguish from changes caused by drug treatment.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

Hagen

Gonçalves

Hedley

et al. 2017

Preprint

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Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences in haplogroup affiliation and nuclear ancestry, genogeophraphic affinity (GGA). This bi-genomic linkage disequilibrium (2GLD) could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation. The extensive 2GLD documented is a major concern when interpreting historic as well as designing future mtDNA association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/149070 doi: bioRxiv preprint first posted online 3 Genetic variants in mitochondrial DNA (mtDNA) -and in nuclear genes coding for mitochondrial function -have been associated with disease 1-3 . More than 300 variants 4,5 in mtDNA and genes involved in mitochondrial function 6 have been reported to cause mitochondrial disease which is clinically characterised by complex metabolic, neurological, muscular and psychiatric symptoms 7,8 .SNPs in mtDNA and mitochondrial haplogroups (mtDNA hgs), which are evolutionarily fixed SNP sets with a characteristic geographical distribution, have been proposed as potential disease modifiers 8 . This has been reported in neurological degenerative diseases such as Alzheimer's disease 9-12 and Parkinson's disease 12-14 , metabolic diseases and cancers 15 , as well as psychiatric diseases, notably schizophrenia (SZ) and bipolar disease [16][17][18] .Association studies of mtDNA variants and disease have been difficult to replicate 8 . However, the definition of a methodological paradigm for association studies with mtDNA variants 19 implicitly assumes that mtDNA variants are independent of the nuclear genome. In a recent Danish study on mtDNA haplogroups and their nuclear ancestry or nuclear genogeographical affinity (GGA), we demonstrated a marked difference in nuclear ancestry between individual haplogroups 20 . This means that mtDNA hgs entail population stratification also at the level of gDNA. The effect of such a stratification on disease association, will depend on the admixture structure of the particular population, the population history, epidemiology and genetic epidemiology of the disease, as well as the number of persons included in the study. The extensive fine-scale heterogeneity of gDNA and significant admixture documented in the UK 21 and Europe 22 further increase the risk of spurious false positive associations, if the mtDNA/gDNA interaction is not corrected phenomenon for in association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The co...

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Mitochondrial DNA (mtDNA) and schizophrenia

Cited by 80 publications

References 154 publications

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia

Postmortem studies on mitochondria in schizophrenia

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

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