Regulators of mitochondrial complex I activity: A review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

Duong, Angela; Che, Yi; Ceylan, Deniz; Pinguelo, Arsène; Andreazza, Ana Cristina; Young, L. Trevor; Berk, Michael

doi:10.1016/j.psychres.2015.12.015

Cited by 8 publications

(7 citation statements)

References 116 publications

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“…The pattern of decreases in levels of complexes I and III, while that of complex IV remains normal, results in increased generation of ROS. Less is known about changes in the mitochondrial electron transport system in acute psychosis and schizophrenia, but especially prominent among pathogenically-related decreased levels of DNA and transcriptional activity in schizophrenia are decreases in complex I genes, proteins and activities 21 , 22 . The significant decreases in levels of complex I protein in brain tissues of schizophrenic patients have been attributed partially to medications 23 .…”

Section: Discussionmentioning

confidence: 99%

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

et al. 2020

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Potentially neurotoxic systems involved in traumatic and degenerative diseases of the brain were assessed in acute psychosis. Astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) were immunoprecipitated from plasma of ten untreated first-episode psychotics (FPs) and ten matched normal controls (Cs). Neural mitochondrial electron transport and complement proteins were extracted, quantified by ELISAs and normalized with levels of CD81 exosome marker. Levels of subunits 1 and 6 of NADH-ubiquinone oxidoreductase (complex I) and subunit 10 of cytochrome b-c1 oxidase (complex III), but not of subunit 1 of cytochrome C oxidase (complex IV) or superoxide dismutase 1 (SOD1) were significantly lower in ADEs and NDEs of FPs than Cs. This dysregulated pattern of electron transport proteins is associated with increased generation of reactive oxygen species. ADE glial fibrillary acidic protein levels were significantly higher in FPs than Cs, indicating a higher percentage of inflammatory astrocytes in FPs. ADE levels of C3b opsonin were significantly higher and those of C5b-9 attack complex was marginally higher in FPs than Cs. A significantly lower ADE level of the C3 convertase inhibitor CD55 may explain the higher levels of C3 convertase-generated C3b. ADE levels of the neuroprotective protein leukemia inhibitory factor (LIF) were significantly lower in FPs than Cs, whereas levels of IL-6 were no different. Plasma neural exosome levels of electron transport and complement proteins may be useful in predicting FP and guiding therapy. SOD mimetics, C3 convertase inhibitors and LIF receptor agonists also may have therapeutic benefits in FP.

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Section: Discussionmentioning

confidence: 99%

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

et al. 2020

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“…These reductions might be the result of an overrepresentation of subjects with chronic antipsychotic medication that reduces complex I activity. To date, very few studies of deficits in complex I have been reported in medication-free subjects as reviewed [5,6,42]. The reports of a deficit in complex I are found in studies of medicated subjects, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, other conditions present in patients might lead to complex I alterations such as metabolic syndrome. It is known that small molecules such as glucose, glutamate, and arachidonic acid can negatively regulate complex I activity [reviewed in [6]]. These speculations will require a cohort of prospective subjects to undergo bioenergetics measurements using noninvasive methods and prior to medications to determine if lower or higher mitochondrial function precedes treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations have been reported in 26 nuclear-encoded and mitochondrial DNA (mtDNA)-encoded genes of complex I that can lead to complex I deficiency disorders [4]. Prior studies have also found deficits in complex I from postmortem brain samples of SZ [5] and BD subjects [6]. Alterations in complex I subunit proteins and genes have also been reported in lymphoblastoid cell lines and fibroblasts from subjects with SZ [5] and BD [7].…”

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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“…One study found state-dependent alterations in sirtuin 1, 2 and 6 in peripheral blood cells of BD and MDD patients. 69 Duong et al 70 aimed to identify mitochondrial complex 1 dysfunction in a BD post-mortem brain sample, but no significant alteration could be determined for Sirt -3. 70 …”

Section: Epigenetic Mechanisms and Findings In Bdmentioning

confidence: 99%

Dissecting bipolar disorder complexity through epigenomic approach

Ludwig

Dwivedi

2016

Mol Psychiatry

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In recent years, numerous studies of gene regulation mechanisms have emerged in neuroscience. Epigenetic modifications, described as heritable but reversible changes, include DNA methylation, DNA hydroxymethylation, histone modifications and noncoding RNAs. The pathogenesis of psychiatric disorders, such as bipolar disorder, may be ascribed to a complex gene–environment interaction (G × E) model, linking the genome, environmental factors and epigenetic marks. Both the high complexity and the high heritability of bipolar disorder make it a compelling candidate for neurobiological analyses beyond DNA sequencing. Questions that are being raised in this review are the precise phenotype of the disorder in question, and also the trait versus state debate and how these concepts are being implemented in a variety of study designs.

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Regulators of mitochondrial complex I activity: A review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

Cited by 8 publications

References 116 publications

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

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

Dissecting bipolar disorder complexity through epigenomic approach

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