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

Rollins, Brandi; Morgan, Ling; Hjelm, Brooke E.; Sequeira, Adolfo; Schatzberg, Alan F.; Barchas, Jack D.; Lee, Francis S.; Myers, R; Watson, Stanley J.; Akil, Huda; Potkin, Steven G.; Bunney, William E.; Vawter, Marquis P.

doi:10.1159/000484348

Cited by 38 publications

(42 citation statements)

References 49 publications

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“…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 . Nonetheless, induced pluripotent stem cell (iPSC) lines of interneurons from schizophrenic patients showed altered expression of genes encoding proteins involved in numerous mitochondrial activities, including increased generation of ROS 24 .…”

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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“…However, the study was limited by a small sample size (18 subjects); the young ages of the subjects, who were minimally exposed to medication; and the recent onset of BD. No differences in complex I activity were found postmortem in prefrontal cortex mitochondria from BD and controls 19. The activity of other complexes or mitochondrial respiration has not been determined.…”

Section: Introductionmentioning

confidence: 85%

“…The activity of other complexes or mitochondrial respiration has not been determined. High complex I activity was found in patients without medication; decreased complex I activity was found in patients with detectable psychotropic medications 19…”

Section: Introductionmentioning

confidence: 95%

Disturbances of mitochondrial parameters to distinguish patients with depressive episode of bipolar disorder and major depressive disorder

Zvěřová¹,

Hroudová²,

Fišar³

et al. 2019

NDT

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BackgroundMitochondrial dysfunctions are implicated in the pathophysiology of mood disorders. We measured and examined the following selected mitochondrial parameters: citrate synthase (CS) activity, electron transport system (ETS) complex (complexes I, II, and IV) activities, and mitochondrial respiration in blood platelets.Patients and methodsThe analyses were performed for 24 patients suffering from a depressive episode of bipolar affective disorder (BD), compared to 68 patients with MDD and 104 healthy controls. BD and unipolar depression were clinically evaluated using well-established diagnostic scales and questionnaires.ResultsThe CS, complex II, and complex IV activities were decreased in the depressive episode of BD patients; complex I and complex I/CS ratio were significantly increased compared to healthy controls. We observed significantly decreased complex II and CS activities in patients suffering from MDD compared to controls. Decreased respiration after complex I inhibition and increased residual respiration were found in depressive BD patients compared to controls. Physiological respiration and capacity of the ETS were decreased, and respiration after complex I inhibition was increased in MDD patients, compared to controls. Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities.ConclusionWe can conclude that complex I and its abnormal activity contribute to the defects in cellular energy metabolism during a depressive episode of BD. The observed parameters could be used in a panel of biomarkers that could selectively distinguish BD depression from MDD and can be easily examined from blood elements.

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“…Together with the activity of Complex I, NDUFB9 has been investigated in other brain areas in SZ [59,60]. Thus, the altered expression of NDUFB9 observed in this study could contribute to reduce energy metabolism in cerebellar cells through the disruption of Complex I in respiratory electron transport and could consequently decrease the propagation action potentials among the major cell types of the cerebellar cortex in chronic SZ.…”

Section: Energy Metabolism Modulementioning

confidence: 68%

Analysis Of Molecular Networks In The Cerebellum In Chronic Schizophrenia: Modulation By Early Postnatal Life Stressors In Murine Models

Vera-Montecinos

Rodriguez‐Mias

MacDowell

et al. 2021

Preprint

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Despite the growing importance of the cortico-cerebellar-thalamo-cortical circuit in schizophrenia, limited information is available regarding altered molecular networks in cerebellum. To identify altered protein networks, we conducted proteomic analysis of grey matter of postmortem cerebellar cortex in chronic schizophrenia subjects (n=12) and healthy individuals (n=14) followed by an extensive bioinformatic analysis. Two double-hit postnatal stress murine models for SZ were used to validate the most robust candidates. The models were maternal deprivation combined with an additional stressor: social isolation or chronic restraint stress. We found that the individual proteomic profile allowed the segregation of most schizophrenia cases from healthy individuals. We found 250 proteins with altered levels. This group was enriched in proteins related to mental disorders, mitochondrial disease, stress, and a number of biological functions including energy, immune response, axonal cytoskeletal organization and vesicle-mediated transport. Network analysis identified three modules: energy metabolism, neutrophil degranulation and a mixed module of mainly axonal-related functions. We analysed the most robust candidates in the networks in two double-hit stress murine models. METTL7A from the degranulation pathway was reduced in both models, while NDUFB9 from the energy network and CLASP1 from the axonal module decreased in only one model. This work provides evidence for altered energy, immune and axonal-related networks in the cerebellum in schizophrenia, suggesting that the accumulation of molecular errors, some by an early postnatal stress exposure, could lead to a failure in the normal cerebellar functions, impairing synaptic response and the defence mechanisms of this region against external harmful injuries in schizophrenia.

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

Cited by 38 publications

References 49 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

Disturbances of mitochondrial parameters to distinguish patients with depressive episode of bipolar disorder and major depressive disorder

Analysis Of Molecular Networks In The Cerebellum In Chronic Schizophrenia: Modulation By Early Postnatal Life Stressors In Murine Models

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