Decreased Cytochrome-c Oxidase Activity and Lack of Age-Related Accumulation of Mitochondrial DNA Deletions in the Brains of Schizophrenics

Cavelier, Lucia; Jazin, Elena; Eriksson, Inger; Prince, Jonathan A.; Båve, Ullvi; Oreland, Lars; Gyllensten, Ulf

doi:10.1006/geno.1995.1234

Cited by 141 publications

(97 citation statements)

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“…A decrease in PFK activity could slow the rate of glycolysis to avoid lactate accumulation under resting conditions, but may influence the ability of cells to meet energy demands during neuronal activation. These findings are consistent with previous reports of abnormal enzyme activity in metabolic pathways in schizophrenia, such as decreased creatine kinase activity, as well as a decrease in cytochrome-c oxidase activity in the caudate nucleus (63%) and frontal cortex (43%) (3, 15, 16). Interestingly, similar changes in enzyme activity were not found in a cohort of MDD subjects.…”

Section: Discussionsupporting

confidence: 93%

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Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-qPCR was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.

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Section: Discussionsupporting

confidence: 93%

“…In schizophrenia, there was decreased first half and increased second half TCA cycle enzyme activity in unpooled DLPFC samples (n=13), as well as decreased specific activity of mitochondrial respiratory chain enzymes in the frontal cortex (1, 15, 16). In vivo studies also implicate alteration of bioenergetic pathways in schizophrenia.…”

Section: Introductionmentioning

confidence: 98%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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“…However, the sensitivity of cytochrome c oxidase to azide and the sensitivity of NADH-cytochrome c reductase to rotenone was decreased in brains of schizophrenic patients. 63 Cavelier and colleagues 64 at Uppsala University examined cytochrome oxidase activity in the brains of schizophrenic patients postmortem and compared them with those of patients with Alzheimer's disease. Activity was significantly decreased in caudate (63%) and frontal cortex (43%) in schizophrenic patients compared with controls.…”

Section: Schizophreniamentioning

confidence: 99%

The other, forgotten genome: mitochondrial DNA and mental disorders

Kato

2001

Mol Psychiatry

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This paper summarizes recent research on mitochondrial DNA (mtDNA)-which might be described as the 'other, forgotten genome'. Recent studies suggest the possible pathophysiological significance of mtDNA in schizophrenia and neurodegenerative and mood disorders. Decreased activity of the mitochondrial electron transport chain has been implicated in both Parkinson's and Alzheimer's disease and while age-related accumulation of mtDNA deletions has been suggested as a possible cause, there is no concrete evidence that particular mtDNA polymorphisms are responsible. In schizophrenia, the activity and/or mRNA expression of complex IV are involved, but the direction of the alteration is not the same and there is no evidence linking schizophrenia with mtDNA. In bipolar disorder, there is some evidence of parent-of-origin effects and association with mtDNA polymorphisms but further investigation is needed to elucidate the role of mtDNA in mental disorders. Molecular Psychiatry (2001) 6, 625-633.

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“…The etiology of schizophrenia is still unknown but recent advances in neuroscience have suggested a wide array of competing mechanisms that may be involved in the disorder, [3][4][5][6] among them altered cerebral energy metabolism 7 and mitochondria dysfunction. [8][9][10][11][12][13][14] Recently, we have shown that platelet mitochondrial complex I, which is the first complex of the mitochondrial electron transport system, is significantly increased in schizophrenic patients in the acute state, and not in patients with affective disorders. 15 In the present study we further demonstrate that complex I activity is altered with disease state presenting high specificity and sensitivity.…”

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confidence: 99%

State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia

et al. 2002

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Keywords: schizophrenia; mitochondrial complex I; human 24-, 51-and 75-kDa subunits of complex I; platelets; biological marker Schizophrenia, the most severe psychiatric disorder, is characterized by heterogeneity of clinical signs, often categorized into positive and negative symptoms. Among a wide array of competing biological mechanisms, altered cerebral energy metabolism and mitochondrial dysfunction have been suggested to play an important role in the pathophysiology of schizophrenia. In this study we investigated mitochondrial complex I in platelets of 113 schizophrenic patients divided into three groups (acute psychotic episode, chronic active state and residual schizophrenia) and 37 control subjects. Complex I was analysed at the level of enzymatic activity, mRNA and protein levels by enzyme kinetics, RT-PCR and Western blot analyses, respectively. Complex I activity in platelets of schizophrenic patients altered with disease state presenting high specificity and sensitivity. Thus, increased activity was associated with psychotic symptomology, while its decrease was observed in patients with residual schizophrenia. The relationship between the clinical state and complex I activity in schizophrenia was further supported by its positive correlation with the severity of patients' positive symptoms assessed by clinical ratings. In addition, similar alterations were observed at the levels of mRNA and protein of the 24-and 51-kDa iron-sulfur flavoprotein subunits of the complex. Taken together these results point to the potential of platelet complex I to turn into a reliable novel marker for schizophrenia. At present, definitive diagnosis depends only on descriptive behavioral and symptomatic information, therefore a peripheral measurable specific marker will contribute to diagnosis and monitoring of the disease. Schizophrenia, is associated with cognitive and emotional decline and a severe reduction in functioning and coping abilities. 1 The heterogeneity and comorbidity with other mental disorders frequently renders schizophrenia difficult to diagnose. 2 Indeed, at present, definitive diagnosis depends only on descriptive behavioral and symptomatic information. Therefore, it is important to develop a biological test for the diagnosis and follow-up of the disorder. The etiology of schizophrenia is still unknown but recent advances in neuroscience have suggested a wide array of competing mechanisms that may be involved in the disorder, 3-6 among them altered cerebral energy metabolism 7 and mitochondria dysfunction. [8][9][10][11][12][13][14] Recently, we have shown that platelet mitochondrial complex I, which is the first complex of the mitochondrial electron transport system, is significantly increased in schizophrenic patients in the acute state, and not in patients with affective disorders. 15 In the present study we further demonstrate that complex I activity is altered with disease state presenting high specificity and sensitivity. In addition, similar alterations were also expressed at the levels of mRN...

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Decreased Cytochrome-c Oxidase Activity and Lack of Age-Related Accumulation of Mitochondrial DNA Deletions in the Brains of Schizophrenics

Cited by 141 publications

References 0 publications

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

The other, forgotten genome: mitochondrial DNA and mental disorders

State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia

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