Mitochondrial Complex I as a Possible Novel Peripheral Biomarker for Schizophrenia

Ben‐Shachar, Dorit

doi:10.1007/978-1-4020-9838-3_6

Cited by 3 publications

(4 citation statements)

References 114 publications

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“…While the mechanism whereby mitochondrial dysfunction may lead to the syndrome of ASD is unclear, it is likely to involve such pathogenic processes as neuroinflammation, glial activation and cytokine release (Hass 2010). Interestingly, mitochondrial dysfunction, and NDUFV1 more specifically, has also been raised in association with the pathogenesis of schizophrenia (Park and Park 2012;Ben-Shachar 2009). Clearly, this is an appropriate avenue for further exploration.…”

Section: Discussionmentioning

confidence: 94%

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

et al. 2014

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Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative 'developmental/neuropsychiatric' susceptibility gene(s), GSTP1 and NDUFV1.

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Section: Discussionmentioning

confidence: 94%

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

et al. 2014

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“…[4][5][6][7][8][9] Therefore, it is not surprising that multifaceted OXPHOS dysfunctions, originating from both genetic (maternal, or mendelian inheritance) and environmental influences, have been reported in many diseases and disorders, including neuropsychiatric disorders such as Alzheimer and Parkinson diseases, schizophrenia (SCZ), and bipolar disorder (BD). 2,[10][11][12] SCZ is a severe mental disorder, heavily affecting the lives of those afflicted and their families. The disorder is characterized by various abnormal cognitive, affective, and motor behavioural features, associated with a variety of impairments in occupational and social functioning.…”

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confidence: 99%

“…These core processes facilitate the brain’s constant interaction with and adaption to the environment and are highly dependent on continuous oxygen supply. 1,2 The latter is evident by high energetic demands and oxygen uptake of the brain, roughly 20% of total body consumption while only about 2% of body’s weight. 3 Energy in the form of adenosine triphosphate (ATP) is generated mainly in mitochondria by the oxidative phosphorylation (OXPHOS) process, in which electrons produced by the citric acid cycle are transferred down the mitochondrial respiratory complexes.…”

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confidence: 99%

Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia

2016

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Mitochondria are key players in the generation and regulation of cellular bioenergetics, producing the majority of adenosine triphosphate molecules by the oxidative phosphorylation system (OXPHOS). Linked to numerous signaling pathways and cellular functions, mitochondria, and OXPHOS in particular, are involved in neuronal development, connectivity, plasticity, and differentiation. Impairments in a variety of mitochondrial functions have been described in different general and psychiatric disorders, including schizophrenia (SCZ), a severe, chronic, debilitating illness that heavily affects the lives of patients and their families. This article reviews findings emphasizing the role of OXPHOS in the pathophysiology of SCZ. Evidence accumulated during the past few decades from imaging, transcriptomic, proteomic, and metabolomic studies points at OXPHOS deficit involvement in SCZ. Abnormalities have been reported in high-energy phosphates generated by the OXPHOS, in the activity of its complexes and gene expression, primarily of complex I (CoI). In addition, cellular signaling such as cAMP/protein kinase A (PKA) and Ca þ2 , neuronal development, connectivity, and plasticity have been linked to OXPHOS function and are reported to be impaired in SCZ. Finally, CoI has been shown as a site of interaction for both dopamine (DA) and antipsychotic drugs, further substantiating its role in the pathology of SCZ. Understanding the role of mitochondria and the OXPHOS in particular may encourage new insights into the pathophysiology and etiology of this debilitating disorder. Abré géLes mitochondries sont un acteur clé dans la génération et la régulation de la bioénergétique cellulaire, produisant la majorité des molécules ATP par le système de phosphorylation oxydative (OXPHOS). Liées à de nombreuses voies de signalisation et fonctions cellulaires, les mitochondries, et OXPHOS en particulier, sont impliqués dans le développement neuronal, la connectivité, la plasticité et la différenciation. Des déficiences d'une variété de fonctions mitochondriales ont été décrites dans différents troubles généraux et psychiatriques, dont la schizophrénie (SCZ), une maladie grave, chronique et débilitante qui affecte lourdement la vie des patients et de leur famille. Cet article passe en revue les résultats mettant l'accent sur le rô le d'OXPHOS dans la pathophysiologie de la SCZ. Les données probantes accumulées au cours des récentes décennies dans des études d'imagerie, transcriptomiques, protéomiques et métabolomiques dénoncent la participation du déficit d'OXPHOS à la SCZ. Des anomalies ont été signalées dans les phosphates à haute énergie produits par le système OXPHOS, dans l'activité de ses complexes et de son expression génétique, principalement du complexe I (CoI). En outre, la signalisation cellulaire, comme

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“…Furthermore, studies investigating gene expression in postmortem brain tissues of individuals with SCZ have consistently revealed a reduction in the expression of mitochondria-related genes. Specifically, genes such as NADH: ubiquinone oxidoreductase core subunit V1 ( NDUFV1 ), NADH: ubiquinone oxidoreductase core subunit V2 ( NDUFV2 ), NADH: ubiquinone oxidoreductase core subunit S1 ( NDUFS1 ) [59–61], and cytochrome c oxidase ( COX ) show decreased expression levels in a region-specific manner [62]. NDUFV2 and multiple isoforms of COX are present in the iNs gene-sets.…”

Section: Discussionmentioning

confidence: 99%

Direct targets ofMEF2Care enriched for genes associated with schizophrenia and cognitive function and are involved in neurogenesis and mitochondrial function

Ali,

Laighneach,

Corley

et al. 2023

Preprint

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Myocyte Enhancer Factor 2C(MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identifiedMEF2Cas a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement ofMEF2Cin these phenotypes using human-derived neural stem cells (NSCs) and induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models,MEF2Cfunction had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data withMEF2CChIP-seq data to identify dysregulated direct target genes ofMEF2Cin the NSCs and iNs models. SeveralMEF2Cdirect target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rarede novomutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the hippocampus and cortex and are involved in a wide range of biological processes including neurogenesis, metabolic processes, protein modifications, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP atMEF2C(rs6893807, which is associated with IQ) on the expression of a target gene,BNIP3L.BNIP3Lis a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption ofMEF2Cdysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neurogenesis and mitochondrial function in the etiology of these phenotypes.Author SummarySchizophrenia is a complex disorder caused by many genes. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability, leading to unemployment, homelessness and social isolation. Genome-wide association studies of schizophrenia and cognitive function have been effective at identifying individual SNPs and genes that contribute to these phenotypes but have struggled to immediately uncover the bigger picture of the underlying biology of the disorder. Here we take an individual gene associated with schizophrenia and cognitive function calledMEF2C, which on its own is a very important regulator of brain development. We use functional genomics data from studies whereMEF2Chas been mutated to identify sets of other genes that are influenced byMEF2Cin developing and mature neurons. We show that several of these gene-sets are enriched for common variants associated with schizophrenia and cognitive function, and for rare variants that increase risk of various neurodevelopmental disorders. These gene-sets are involved in neurogenesis and mitochondrial function, providing evidence that these biological processes may be important in the context of the molecular mechanisms that underpin schizophrenia and cognitive function.

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Mitochondrial Complex I as a Possible Novel Peripheral Biomarker for Schizophrenia

Cited by 3 publications

References 114 publications

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia

Direct targets ofMEF2Care enriched for genes associated with schizophrenia and cognitive function and are involved in neurogenesis and mitochondrial function

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