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Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.

One of the prevailing hypotheses suggests schizophrenia as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems. Accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. An attractive model to study processes related to neurodevelopment in schizophrenia is reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into different neuronal lineages. iPSCs from three schizophrenia patients and from two controls were reprogrammed from hair follicle keratinocytes, because of their accessibility and common ectodermal origin with neurons. iPSCs were differentiated into Pax6 + /Nestin + neural precursors and then further differentiated into β3-Tubulin + /tyrosine hydroxylase + /DAT + dopaminergic neurons. In addition, iPSCs were differentiated through embryonic bodies into β3-Tubulin + /Tbox brain1 + glutamatergic neurons. Schizophrenia-derived dopaminergic cells showed severely impaired ability to differentiate, whereas glutamatergic cells were unable to maturate. Mitochondrial respiration and its sensitivity to dopamine-induced inhibition were impaired in schizophrenia-derived keratinocytes and iPSCs. Moreover, we observed dissipation of mitochondrial membrane potential (Δψ m ) and perturbations in mitochondrial network structure and connectivity in dopaminergic along the differentiation process and in glutamatergic cells. Our data unravel perturbations in neural differentiation and mitochondrial function, which may be interconnected, and of relevance to dysfunctional neurodevelopmental processes in schizophrenia.

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.

The regulation of gene expression has been implicated in the etiology and treatment of depression. Transcription factors serve as the intermediates between intracellular cascades and gene expression, and may therefore be involved in the pathophysiology and pharmacotherapy of depression. We and others have previously reported an increase in the phosphorylation of the transcription factor cAMP response element binding protein (CREB) by antidepressants, alongside brain region-specific alterations in pCREB by stress. In the present study, we examined the expression of another member of the CREB/ATF family of transcription factors, ATF2, in the brains of rats chronically treated with two different antidepressants, and in rats 4 months after their exposure to prolonged stress. ATF2 phosphorylation was decreased by antidepressants and increased at the aftermath of prolonged stress, specifically in the frontal cortex. We also examined ATF2 expression in the ventral parieto-occipital region of post-mortem human brains of normal controls, depressed, bipolar, and schizophrenic patients, obtained from the Stanley Foundation Brain Consortium. No alterations were observed in the levels of ATF2. However, in the depressed group, the pATF2 levels were higher in unmedicated compared to medicated patients, suggesting an antidepressant-induced reduction in pATF2. We discuss the possible role of ATF2 in depression, and propose that an interplay between ATF2 and CREB, and possibly other transcription factors, determines the final gene expression pattern in the etiology and treatment of depression.

Negative symptoms in schizophrenia are associated with decreased dopaminergic activity in the prefrontal cortex (PFC). It is hypothesized that increasing dopamine levels would alleviate negative symptoms. Termination of dopamine activity in the PFC is mainly via catechol-O-methyl tranferase (COMT) activity. Hence, inhibition of COMT activity with entacapone should reverse PFC dopaminergic transmission. To assess the efficacy of entacapone addition to antipsychotic treatment in patients with residual schizophrenia, we conducted a double-blind, randomised, placebo-controlled study for 12 wk of treatment with entacapone or placebo. Clinical measures (PANSS, CGI and QLS) were obtained at baseline and at weeks 4, 8 and 12 and cognitive functions were assessed by the RBANSS. Significant improvement over time in PANSS and QLS scores was observed in both groups. However, entacapone did not demonstrate a beneficial effect compared to placebo. Therefore, this study does not support a therapeutic role for entacapone in residual schizophrenia.

Dopamine is a major neurotransmitter in the central nervous system, and its receptors are associated with a number of neuropathological disorders such as Parkinson's disease and schizophrenia. Although the precise pathophysiology of schizophrenia remains unknown, the dopaminergic hypothesis of the illness assumes that the illness results from excessive activity at dopamine synapses in the brain. Because, at present, the diagnosis of schizophrenia relies on descriptive behavioral and symptomatic information, a peripheral measurable marker may enable a simpler, more rapid, and more accurate diagnosis and monitoring. In recent years, human peripheral blood lymphocytes have been found to express several dopamine receptors (D 3 , D 4 , and D 5 ) by using molecular biology techniques and binding assays. It has been suggested that these dopamine receptors found on lymphocytes may reflect receptors found in the brain. Here we demonstrate a correlation between the D 3 dopamine receptor on lymphocytes and schizophrenia and show a significant elevation of at least 2-fold in the mRNA level of the D 3 , but not of the D 4 , dopamine receptor in schizophrenic patients. This increase is not affected by different antipsychotic drug treatments (typical or atypical). Moreover, nonmedicated patients exhibit the same pattern, indicating that this change is not a result of medical treatment. We propose the D 3 receptor mRNA on blood lymphocytes as a marker for identification and followup of schizophrenia.

It is believed that dopamine and alterations of energy metabolism in cortical and subcortical structures are involved in the pathophysiology of schizophrenia. Recently, we and others have shown that dopamine may affect energy metabolism by interacting with mitochondrial complex I activity in rats both in vivo and in vitro. In this study activity of complexes I and IV was assessed in mitochondria isolated from blood platelet of schizophrenic patients and compared to patients with affective disorders and healthy control subjects. Seventy-seven in-patients who met DSM-IV criteria for schizophrenia (in acute exacerbation), bipolar disorder depressed type (BP), or recurrent major depressive disorder (MDD) and 24 control subjects participated in the study. A highly significant increase (240%, p < 0.001) in complex I activity but not in complex IV, was detected in medicated and unmedicated schizophrenic patients compared to controls. No such change was observed in patients with affective disorders. The data demonstrate a specific and selective, alteration in platelet complex I activity in schizophrenic patients, which is not related to medication. If this abnormality in platelet mitochondria reflects brain alterations, it may further support the relevance of alterations in energy metabolism to the pathophysiology of schizophrenia. Finally in the lack of any clinically relevant biological marker for schizophrenia, complex I activity in platelets might become a useful peripheral marker for this disorder.

Transcranial magnetic stimulation (TMS), which is produced by strong non-static magnetic fields, is a non-invasive means to stimulate the cerebral cortex. Studies from recent years show that TMS affects mood in healthy subjects and improves depressive symptoms in patients with major depression. However, the relationship between the clinical efficacy of TMS and stimulation parameters is still obscure. In the present study we have investigated the effects of different stimulation frequencies and number of treatments on catecholamine turnover in SH-SY5Y cell cultures. A single session of magnetic stimulation (1.7 T) caused a significant decrease in intracellular dopamine and L-DOPA and in noradrenaline (NE) release at a rate of 3 Hz for 10 s but increased NE release at a rate of 9 Hz. These alterations were associated with a reduction (47.8%) or an increase (48%) in tyrosine hydroxylase (TH) activity after 3 and 9 Hz magnetic stimulation, respectively. The latter may be related to the known sensitivity of TH to neuronal firing rates and NE concentrations. Higher stimulation frequencies (15, 20, 45 Hz) had no effect on catecholamine metabolism. Unlike 3 Hz acute treatment, chronic treatment (3 Hz, 11 sessions, for 4 d) had no effect on monoamines and TH activity was increased by 54.5% with no change in its protein level. The results of the present study demonstrate that in tissue culture system frequency and treatment duration of the magnetic stimulation are important factors in affecting catecholamine turnover. Considering the major role of catecholamine in the pathophysiology of depression, these findings may be of relevance to the application of rTMS in humans with major depression.

Recently, the dopamine D3-receptor mRNA on blood lymphocytes and platelet mitochondrial complex I were suggested as biological markers of schizophrenia in adults. We investigated the mRNA level of the dopamine D3-receptor and complex I subunits in whole blood cells of early-onset schizophrenic patients compared to healthy controls using quantitative real-time PCR. We found an increased mRNA expression of the complex I 75-kDa subunit (referred to beta-actin in schizophrenic patients (0.57 +/- 0.24 versus 0.23 +/- 0.18 in controls, P < 0.01)), but were unable to analyse the dopamine D3-mRNA expression. This increase appears to be inherent to schizophrenia, because it was found in neuroleptic-naive patients and it was not affected by neuroleptic treatment. Our preliminary findings suggest the mitochondrial complex I as a potential peripheral marker of schizophrenia and its involvement in the pathophysiology of this illness.

Mitochondrial transplantation is currently being explored as a means to repair and restore proper organelle function in a variety of inherited and acquired disorders of energy metabolism. The optimal preparation and application of donor mitochondria is unknown, but most studies in vivo have used injection techniques or, for tissue studies, unpackaged mitochondria (organelles isolated and suspended in buffer) in transplant experiments. Packaging in lipid rafts can increase recipient cell uptake of some compounds and objects. We present the first data comparing recipient cell uptake of unpackaged mitochondria to recipient cell uptake of mitochondria packaged in cell membrane lipids. Mitochondria and membranes were prepared from autologous cells and applied to cells (fibroblasts) in culture. Both unpackaged and lipid-packaged mitochondria were taken into recipient cells and the donor mitochondria showed evidence, in each case, of retained functionality and the ability to merge with the recipient mitochondrial matrix. However, lipid packaging appeared to enhance the uptake of functional mitochondria. Current studies of mitochondrial transplantation in animal models might fruitfully explore the utility and efficacy of lipid-packaged mitochondria in transplant experiments.