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

Abstract

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...

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

“…In the ACC gray matter, the 13 kDa-B subunit of Complex 1 is decreased 1.944 fold in schizophrenia compared to controls. This is in corroboration with previous studies, which report lower activity of complex 1 in the temporal cortex, basal ganglia 29 and in platelets of patients with residual schizophrenia 35 as well as diminished mRNA levels in the dentate gyrus 34 and reduced level of protein in both the gray and white matter proteomes of the PFC in schizophrenia. 18 Dror et al further found complex 1 activity to be associated with psychotic symptomatology.…”

“…18 Dror et al further found complex 1 activity to be associated with psychotic symptomatology. 35 In addition, the gene encoding the 13 kDa-B subunit, located on chromosome 7, has also previously been associated with schizophrenia. 36,37 The reduced abundance of enzymes involved in each stage of cellular respiration suggests depleted glucose metabolism leading to oxidative stress of the ACC in the pathology of schizophrenia.…”

New variants in the mitochondrial genomes of schizophrenic patients

“…Several studies indicate that ND4 is essential for the assembly of complex I 29 and could be involved in the ion channel formation for H þ pumping within the enzyme 30 and the introduction of a histidine in position 446 of the ND4 subunit could affect NADH-ubiquinone oxidoreductase activity. Since complex I activity in schizophrenic patients has been related to psychotic symptomatology, 31 we suggest that the MTND4 12096T4A mutation could participate in this relationship. The fact that this mutation is not found in homoplasmy also reflects the importance of the change in the microenvironment of the protein.…”

Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics

“…These proteins belonged to the glycolytic pathway [110] , indicating that impaired glycolytic response could be a potential early stage of diagnostic biomarker for Sz. Mitochondrial complex Ⅰ, the first enzyme in the mitochondrial respiratory chain for the oxidation of glucose, was found to have increased activity in the platelets from people with Sz [108] and to have higher mRNA levels in blood from people with Sz [111,113] . It has also been reported that the activity of platelet mitochondrial complex Ⅰ is associated with positive symptoms and clinical disease course in people with Sz [108] .…”