Diverse roles of mtDNA in schizophrenia: Implications in its pathophysiology and as biomarker for cognitive impairment

Suárez-Méndez, Samuel; Cruz, Dulce Dajheanne García-de la; Tovilla‐Zárate, Carlos Alfonso; Genis‐Mendoza, Alma Delia; Ramón-Torres, Rosa Angélica; González‐Castro, Thelma Beatriz; Juárez‐Rojop, Isela Esther

doi:10.1016/j.pbiomolbio.2020.04.004

Cited by 13 publications

(4 citation statements)

References 62 publications

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“…Mitochondria are essential for neuronal activity and plasticity, and mitochondrial dysfunction leads to cortical under-connectivity: reduced dendrite, axon and synapse growth( Fernandez et al, 2019 ). Meanwhile, abnormalities in mitochondrial structure and function have been observed in psychiatric disease( Clay et al, 2011 ), and cell-free mitochondrial DNA fragment could be used as a biomarker for cognitive deficits in schizophrenia( Suárez-Méndez et al, 2020 ).…”

Section: Mechanisms Connecting Brain Insulin Resistance and Cognitive Deficitsmentioning

confidence: 99%

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Chen

Cao

et al. 2021

Front. Pharmacol.

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Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized.

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Section: Mechanisms Connecting Brain Insulin Resistance and Cognitive Deficitsmentioning

confidence: 99%

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Chen

Cao

et al. 2021

Front. Pharmacol.

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“…Ультраструктурные повреждения митохондрий в виде набухания крист и снижения количества митохондрий в микроглии при шизофрении, обнаруженные в настоящем исследовании, могут быть связаны с нарушенной экспрессией митохондриальных генов, найденной в префронтальной коре у больных шизофренией, не принимавших нейролептики [49,50], мутациями митохондриальной ДНК [51,52]. Эти данные показывают, что дефицит митохондрий в микроглии, по-видимому, не связан с влиянием антипсихотической терапии.…”

Section: повреждения митохондрий связаны с патогенезом шизофренииunclassified

Microglial Reactivity in the Prefrontal Cortex in Schizophrenia

Uranova,

Vikhreva

2023

Psychiatry

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Background: schizophrenia is associated with neuroinflammation and dysregulation of the immune system involving microglia. The study of microglial reactivity in schizophrenia is at an early stage. The results of neuroimaging and postmortem studies are contradictory. Aim of the study: to analyze and summarize the results of morphometric studies of the microglial reactivity at the ultrastructural level in postmortem prefrontal cortex in schizophrenia compared to healthy controls. Material and methods: the study was performed in layer 5 of the prefrontal cortex in 21 cases of schizophrenia and 20 control cases using transmission electron microscopy and morphometry. Results and conclusion: we found that chronic schizophrenia is characterized by a combination of signs of activation, progressive dystrophy and accelerated aging of microglia. The reactivity of microglia in schizophrenia is associated with age, the age of onset of the disease, the duration of the disease and the type of course of the disease, which indicates the participation of microglia in the pathological process in schizophrenia. Damage and deficit mitochondria and the disturbance of energy metabolism can play a key role in microglial dysfunction in schizophrenia.

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“…C-cfDNA isolated from healthy subjects contains approximately 54% of GC pairs [ 34 ] compared to 42% in gDNA [ 35 ]. The content of such gc-DNA as mitochondrial DNA (mtDNA) and the ribosomal repeat (rDNA) in c-cfDNA significantly increases in pathology or external influences, which are accompanied by chronic oxidative stress and upregulated cell death [ 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

“…All the studies reported a two- to three-fold c-cfDNA increase in SZ patients. The concentrations of mtDNA [ 38 ], rDNA [ 7 ], GC-rich Alu repeats [ 50 ], and oxy-DNA [ 6 ] in the blood plasma of SZ patients exceeded the concentrations in the blood plasma of healthy controls (hc-cfDNA).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Analysis of Biological Activity of Circulating Cell-Free DNA Isolated from Blood Plasma of Schizophrenic Patients and Healthy Controls

Ershova

Shmarina

Porokhovnik

et al. 2022

Genes

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Schizophrenia is associated with low-grade systemic inflammation. Circulating cell-free DNA (c-cfDNA) belongs to the DAMP class. The major research question was: can the c-cfDNA of schizophrenic patients (sz-cfDNA) stimulate the DNA sensor genes, which control the innate immunity? We investigated the in vitro response of ten human skin fibroblast (HSF) lines to five DNA probes containing different amounts of a GC-rich marker (the ribosomal repeat) and a DNA oxidation marker (8-oxodG) including sz-cfDNA and healthy control c-cfDNA (hc-cfDNA) probes. After 1 h, 3 h, and 24 h of incubation, the expression of 6 protein genes responsible for cfDNA transport into the cell (EEA1 and HMGB1) and the recognition of cytosolic DNA (TLR9, AIM2, STING and RIG-I) was analyzed at the transcriptional (RT-qPCR) and protein level (flow cytometry and fluorescence microscopy). Additionally, we analyzed changes in the RNA amount of 32 genes (RT-qPCR), which had been previously associated with different cellular responses to cell-free DNA with different characteristics. Adding sz-cfDNA and hc-cfDNA to the HSF medium in equal amounts (50 ng/mL) blocked endocytosis and stimulated TLR9 and STING gene expression while blocking RIG-I and AIM2 expression. Sz-cfDNA and hc-cfDNA, compared to gDNA, demonstrated much stronger stimulated transcription of genes that control cell proliferation, cytokine synthesis, apoptosis, autophagy, and mitochondrial biogenesis. No significant difference was observed in the response of the cells to sz-cfDNA and hc-cfDNA. Sz-cfDNA and hc-cfDNA showed similarly high biological activity towards HSFs, stimulating the gene activity of TLR9 and STING DNA sensor proteins and blocking the activity of the AIM2 protein gene. Since the sz-cfDNA content in the patients’ blood is several times higher than the hc-cfDNA content, sz-cfDNA may upregulate pro-inflammatory cytokines in schizophrenia.

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Diverse roles of mtDNA in schizophrenia: Implications in its pathophysiology and as biomarker for cognitive impairment

Cited by 13 publications

References 62 publications

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Microglial Reactivity in the Prefrontal Cortex in Schizophrenia

In Vitro Analysis of Biological Activity of Circulating Cell-Free DNA Isolated from Blood Plasma of Schizophrenic Patients and Healthy Controls

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