Mitochondrial Complex I Activity and Oxidative Damage to Mitochondrial Proteins in the Prefrontal Cortex of Patients With Bipolar Disorder

Andreazza, Ana Cristina; Shao, Li; Wang, Junfeng; Young, L. Trevor

doi:10.1001/archgenpsychiatry.2010.22

Cited by 386 publications

(263 citation statements)

References 66 publications

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“…Three of them, Cox5a, Ndufab1, and Ndufs7, all found to be upregulated in the present study both in the microarray data and by realtime PCR, were previously reported to be associated with Li treatment (McQuillin et al, 2007) and bipolar disorder (Andreazza et al, 2010;Konradi et al, 2004;Sun et al, 2006;Washizuka et al, 2005;WTCCC, 2007). However, these results need to be considered with caution.…”

Section: Discussionsupporting

confidence: 66%

“…On the basis of our microarray results and previous reports of reduced mitochondrial function in bipolar patients (Andreazza et al, 2010;Stork and Renshaw, 2005), we hypothesized that chronic mild inhibition of oxidative phosphorylation would induce a bipolar disorder-like behavioral phenotype that would be ameliorated by chronic lithium treatment. Chronic treatment with rotenone, an oxidative phosphorylation complex I inhibitor, is used to model Parkinson's disease.…”

Section: Rotenone-induced Behavioral Effectsmentioning

confidence: 72%

“…In the second part of the present study, we aimed to model the reported mitochondrial dysfunction in bipolar patients (Andreazza et al, 2010;Konradi et al, 2004;Stork and Renshaw, 2005) using chronic low doses of rotenone. This reflects the concept that the disorder involves a gradual decrease in mitochondrial function, with symptoms beginning only when a threshold is reached or when an event occurs which requires fully functional cells, making the subject more vulnerable to environmental factors targeting mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

“…Three of these genes, Cox5a, Ndufs7, and Ndufab1, have previously been indicated by at least two independent studies to be upregulated by lithium treatment, downregulated in bipolar patients or genetically associated with bipolar disorder (Andreazza et al, 2010;Konradi et al, 2004;Sun et al, 2006;Washizuka et al, 2005;WTCCC, 2007). We performed quantitative real-time PCR analysis of Cox5a, Ndufs7, and Ndufab1 in the frontal cortex of IMPA1 KO mice, SMIT KO mice and their WT Li-treated and untreated littermates (Supplementary Figure S10A and B).…”

Section: Single Gene Expressionmentioning

confidence: 97%

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Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

Toker

Bersudsky

Plaschkes

et al. 2013

Neuropsychopharmacol

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The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithiumtreated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.

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Section: Discussionsupporting

confidence: 66%

Section: Rotenone-induced Behavioral Effectsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Single Gene Expressionmentioning

confidence: 97%

See 2 more Smart Citations

Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

Toker

Bersudsky

Plaschkes

et al. 2013

Neuropsychopharmacol

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“…Mais recentemente, estudos post-mortem apoiaram essa noção. Tanto alterações no complexo I quanto reduções nos níveis de glutationa foram detectadas no transtorno bipolar 64,65 .…”

Section: Estresse Oxidativounclassified

Marcadores periféricos e a fisiopatologia do transtorno bipolar

Magalhães¹,

Fries²,

Kapczinski³

2012

Rev. psiquiatr. clín.

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Introdução: O entendimento da fisiopatologia do transtorno bipolar vem tendo avanços consistentes nos últimos anos. Um enfoque na relação entre carga alostática e alterações sistêmicas vem tomando corpo, com o objetivo de se entender a frequente progressão da doença. Proeminentes entre os mediadores periféricos têm sido as moléculas que poderiam ser amplamente agrupadas em neurotrofinas, marcadores de estresse oxidativo e marcadores inflamatórios. Objetivo: Descrever achados recentes em relação à fisiopatologia sistêmica do transtorno bipolar, com enfoque especial em estudos brasileiros, tentando articular uma visão coerente do conhecimento atual do campo. Método: Revisão narrativa da literatura relacionada a neurotrofinas, estresse oxidativo e marcadores inflamatórios no transtorno bipolar. Resultados: Diversas fontes de evidência, provenientes tanto de estudos pré-clínicos quanto clínicos, revelam consistentemente alterações sistêmicas no transtorno bipolar. Os achados são especialmente robustos em pacientes com múltiplos episódios. Nesses, alterações relacionadas a episódios de mania e depressão são notáveis em neurotrofinas e dano oxidativo a lipídeos. Um número menor de estudos mostra alterações no sistema imune, em particular estados pró-inflamatórios. Conclusão: Alterações sistêmicas que correlacionam o transtorno bipolar a comorbidade clínica, disfunção cognitiva, incapacidade e mortalidade precoce começam a ser traçadas. Estudos envolvendo desenhos longitudinais, amostras populacionais e ensaios clínicos envolvendo marcadores periféricos devem ser incorporados no futuro próximo e reforçar a validade de uma noção de envolvimento multissistêmico no transtorno bipolar.Magalhães PVS, et al. / Rev Psiq Clín. 2012;39(2):60-7 Palavras-chave: Transtorno bipolar, inflamação, estresse oxidativo, neurotrofinas, fator neurotrófico derivado do cérebro, fisiopatologia, biomarcadores. ABSTRACT Introduction:The understanding of the pathophysiology of bipolar disorder has steadily advanced in the past few years. Thereby, a focus on allostatic load and systemic changes has appeared, with the aim to understand illness progression. Amongst the peripheral markers, molecules that can be widely classified into neurotrophins, oxidadive stress markers, and inflammation markers have been elevated. Objective: To describe recent findings regarding the systemic pathophysiology of bipolar disorder, with a special focus on Brazilian studies and to create a coherent view of the current knowledge in the field. Method: Narrative review of the literature regarding neurotrophins, oxidative stress, and inflammatory markers in bipolar disorder. Results: A diverse body of evidence, based on both pre-clinical and clinical studies, reveals consistent systemic changes in bipolar disorder. The findings are particularly robust in patients after multiple episodes. Thereby, remarkable changes related to manic and depressive episodes were found in neurotrophins and oxidative damage to lipids. Regarding to immune system alterations, in particular pro...

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Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder

et al. 2019

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IMPORTANCE Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B V T), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala. OBJECTIVE To investigate whether MAO-B V T is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [ 11 C]SL25.1188 positron emission tomography scanning to measure MAO-B V T. All participants were drug and medication free, nonsmoking, and otherwise healthy. MAIN OUTCOMES AND MEASURES The MAO-B V T in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B V T in the PFC and duration of major depressive disorder illness. RESULTS Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B V T in the PFC (mean, 26%; analysis of variance, F 1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B V T in the PFC (analysis of covariance, F 1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus. CONCLUSIONS AND RELEVANCE Fifty percent (10 of 20) of patients with MDEs had MAO-B V T values in the PFC exceeding those of healthy controls. Greater MAO-B V T is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

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Mitochondrial Complex I Activity and Oxidative Damage to Mitochondrial Proteins in the Prefrontal Cortex of Patients With Bipolar Disorder

Abstract: Impairment of complex I may be associated with increased protein oxidation and nitration in the prefrontal cortex of patients with bipolar disorder. Therefore, complex I activity and mitochondrial dysfunction may be potential therapeutic targets for bipolar disorder.

Cited by 386 publications

References 66 publications

Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

Inositol-Related Gene Knockouts Mimic Lithium’s Effect on Mitochondrial Function

Marcadores periféricos e a fisiopatologia do transtorno bipolar

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder

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