Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

Hjelm, Brooke E.; Rollins, Brandi; Mamdani, Firoza; Lauterborn, Julie C.; Kirov, George; Lynch, Gary; Gall, Christine M.; Sequeira, Adolfo; Vawter, Marquis P.

doi:10.1159/000441252

Cited by 82 publications

(75 citation statements)

References 123 publications

(183 reference statements)

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“…The observation that mtDNA copy number is altered in the brains of subjects with SZ is in the opposite direction of those studies showing reduced density of mitochondria in SZ brain using different methods, i.e. electron microscopy and immunohistochemistry [18,35,36,37,38]. Our measure of mtDNA copy number is quantitative, but does not yield size and location, both of which may be critical aspects of the mitochondrial dysfunction in these cases.…”

Section: Discussionmentioning

confidence: 55%

“…In a recent review of proteomic, transcriptomic, and genetic studies relevant to SZ, we reported that >250 MitoCarta genes had been shown to be significant in at least one study relevant to SZ [18]. Alterations in these genes could cause mitochondrial dysfunction, although predicting the exact direction and aspect of mitochondrial dysfunction is difficult.…”

Section: Discussionmentioning

confidence: 99%

“…after treatment with risperidone, the responders continued to show a decrease in mitochondria DNA copy number compared with nonresponders. In a large study of peripheral blood samples [18] we observed a significant reduction ( p < 10 -40 ) in mtDNA copy number in SZ subjects compared to controls, as well as a significant reduction in BD ( p < 10 -6 ). However, demographic data for these findings from the GAIN dataset have not been available for analysis.…”

Section: Introductionmentioning

confidence: 91%

“…We have previously reported alterations in mitochondria puncta co-localized with the postsynaptic density compartment of postmortem brain, suggesting mitochondrial density, or size may be affected in SZ [18]. In peripheral samples such as blood, mtDNA copy number has been observed to be decreased in first-episode neuroleptic-naïve subjects with SZ [19].…”

Section: Introductionmentioning

confidence: 99%

“…However, demographic data for these findings from the GAIN dataset have not been available for analysis. We also analyzed a Bulgarian family trios dataset [20] using the same approach, but did not find a significant difference in mtDNA copy number in SZ compared to unaffected controls [18]. These studies using peripheral tissues such as blood, however, do not necessarily correlate with what mtDNA changes may be occurring in SZ brains.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

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Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA “common deletion” in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Rollins¹,

Morgan²,

Hjelm³

et al. 2017

Complex Psychiatry

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Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell–Derived Cerebral Organoids in Schizophrenia

et al. 2020

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IMPORTANCE Three-dimensional cerebral organoids generated from patient-derived induced pluripotent stem cells (iPSCs) may be used to interrogate cellular-molecular underpinnings of schizophrenia.OBJECTIVE To determine transcriptomic profiles and functional characteristics of cerebral organoids from patients with schizophrenia using gene expression studies, complemented with investigations of mitochondrial function through measurement of real-time oxygen consumption rate, and functional studies of neuronal firing with microelectrode arrays. DESIGN, SETTING, AND PARTICIPANTSThis case-control study was conducted at Massachusetts General Hospital between 2017 and 2019. Transcriptomic profiling of iPSC-derived cerebral organoids from 8 patients with schizophrenia and 8 healthy control individuals was undertaken to identify cellular pathways that are aberrant in schizophrenia. Induced pluripotent stem cells and cerebral organoids were generated from patients who had been diagnosed as having schizophrenia and from heathy control individuals.MAIN OUTCOMES AND MEASURES Transcriptomic analysis of iPSC-derived cerebral organoids from patients with schizophrenia show differences in expression of genes involved in synaptic biology and neurodevelopment and are enriched for genes implicated in schizophrenia genome-wide association studies (GWAS). RESULTSThe study included iPSC lines generated from 11 male and 5 female white participants, with a mean age of 38.8 years. RNA sequencing data from iPSC-derived cerebral organoids in schizophrenia showed differential expression of genes involved in synapses, in nervous system development, and in antigen processing. The differentially expressed genes were enriched for genes implicated in schizophrenia, with 23% of GWAS genes showing differential expression in schizophrenia and control organoids: 10 GWAS genes were upregulated in schizophrenia organoids while 15 GWAS genes were downregulated. Analysis of the gene expression profiles suggested dysregulation of genes involved in mitochondrial function and those involved in modulation of excitatory and inhibitory pathways. Studies of mitochondrial respiration showed lower basal consumption rate, adenosine triphosphate production, proton leak, and nonmitochondrial oxygen consumption in schizophrenia cerebral organoids, without any differences in the extracellular acidification rate. Microelectrode array studies of cerebral organoids showed no differences in baseline electrical activity in schizophrenia but revealed a diminished response to stimulation and depolarization.CONCLUSIONS AND RELEVANCE Investigations of patient-derived cerebral organoids in schizophrenia revealed gene expression patterns suggesting dysregulation of a number of pathways in schizophrenia, delineated differences in mitochondrial function, and showed deficits in response to stimulation and depolarization in schizophrenia.

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Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

Tran

Crowley

et al. 2021

JAMA Psychiatry

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that underlie variable penetrance for neuropsychiatric illness in the context of genetic variants that carry elevated risk can advance novel treatment approaches for these disorders.OBJECTIVE To test the hypothesis that mitochondrial compensation is associated with the variable penetrance of schizophrenia in the 22q11.2 deletion syndrome (22q11DS). DESIGN, SETTING, AND PARTICIPANTSThis case-control study compared measures of mitochondrial function and the expression of related genes in 14 induced pluripotent stem cell-derived neurons from typically developing control individuals (6 lines) and from adults with 22q11DS (8 lines). The individuals with 22q11DS included 2 groups, those carrying a diagnosis of schizophrenia and those without this diagnosis (4 lines each). Similar measures were made of lymphoblastic cells lines (LCLs) from a separate group of adults with 22q11DS with (10 lines) or without (8 lines) schizophrenia. The study included samples derived from a clinical setting. The induced pluripotent stem cell lines were derived from individuals with 22q11DS with or without a diagnosis of schizophrenia at Stanford University. The LCLs were from adults within the 22q and You Center at the Children's Hospital of Philadelphia. Data were analyzed between July 1, 2019, and January 24, 2021.MAIN OUTCOMES AND MEASURES Total adenosine triphosphate (ATP), oxidative phosphorylation (OXPHOS) complex activity, and messenger RNA expression via reverse transcription-polymerase chain reaction of selected genes encoding for mitochondrial proteins.RESULTS Study participants included men and women aged 18 to 37 years. Of 32 participants, the mean (SD) age of men was 27 (1.9) years and of women was 29 (1.2) years. Replicating a previous study, neurons from the 22q11DS and schizophrenia (22q+Sz) group had reduced ATP levels (mean [SD], 15.6 [1.5] vs 21.9 [1.4]; P = .02) and reduced OXPHOS activity (ie, complex I; 1.51 [0.1] vs 1.89 [0.1]; P = .01). These deficits were not present in neurons from individuals with 22q11DS without schizophrenia (22q[−]Sz). In this group, the expression of multiple genes encoding OXPHOS subunits was significantly upregulated. For example, compared with control individuals, NDUFV2 expression was increased by 50% in the 22q(−)Sz group (P < .001) but not significantly changed in the 22q+Sz group. Expression of genes driving mitochondrial biogenesis, including PGC1α, showed a similar pattern of upregulation in the 22q(−)Sz group compared with the control and the 22q+Sz groups. Stimulation of mitochondrial biogenesis normalizes the ATP deficit seen in 22q+Sz neurons. Finally, using LCLs from a separate group of adults with 22q11DS, evidence for enhanced mitochondrial biogenesis was again found in the 22q(−)Sz group. CONCLUSIONS AND RELEVANCEIn this study, an increase in mitochondrial biogenesis and function was associated with the absence of schizophrenia in neurons and LCLs from individuals with 22q11DS, but the deficit in the 22q+Sz group was reversible by agents that enhance mitochondrial biogenesis....

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Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

Cited by 82 publications

References 123 publications

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell–Derived Cerebral Organoids in Schizophrenia

Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia

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