Circulating Cell-Free Mitochondrial DNA in Plasma of Individuals with Schizophrenia and Cognitive Deficit in Mexican Population.

Purpose: Cognitive domains are affected in patients with schizophrenia. Mitochondrial dysfunction has been proposed as a possible origin of these symptoms. Cell-free mitochondrial DNA (cf-mtDNA) is an indicator of cellular stress, and it can be identified in individuals with age-associated disorders, this study aimed to explore the presence of cf-mtDNA in plasma of schizophrenia patients and its association with cognitive deficit. Patients and Methods: Ninety-nine subjects were clinically evaluated; the case group included 60 patients diagnosed with schizophrenia and 39 randomly-individuals without psychiatric disorders were included in the comparison group. Cognitive status (MoCA scale) and cell-free mtDNA in blood plasma were assessed and quantified in both groups. Results: From the original sample, cf-mtDNA was identified in 43 subjects, 40 patients with schizophrenia and 3 controls (Χ2 = 31.10, p-value < 0.0001). Thirty-nine out of forty patients with schizophrenia had a cognitive deficit. Conclusion: According to our findings, cognitive impairment and presence of cf-mtDNA were related in subjects with schizophrenia. Thus, while the cognitive deficit might reflect an accelerated aging process, the cf-mtDNA plays a role as a potential biomarker in this mechanism.

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

Schizophrenia (SZ) is a mental disorder characterized by neurocognitive dysfunctions and a reduction in occupational and social functioning. Several studies have provided evidence for mitochondrial dysfunction in the pathophysiology of SZ. In this sense, it is known that the addition of genetic variations in mitochondrial DNA (mtDNA) impairs oxidative phosphorylation of enzymatic complexes in mitochondria, resulting in ATP depletion and subsequent enhancement of reactive oxygen species; this is associated with cellular degeneration and apoptosis observed in some neuropsychiatric disorders. As a consequence of mitochondrial dysfunction, an increase in circulating cell-free mtDNA fragments can occur, which has been observed in individuals with SZ. Moreover, due to the bacterial origin of mitochondria, these cell-free mtDNA fragments in blood plasma may induce inflammatory and immunogenic responses, especially when their release is enhanced in specific disease conditions. However, the exact mechanism by which mtDNA could be released into blood plasma is not yet clear. Therefore, the aims of this review article were to discuss the participation of mtDNA genetic variations in physiopathologic mechanisms of SZ, and to determine the status of the disease and the possible ensuing changes over time by using circulating cell-free mtDNA fragments as a biomarker.

High polygenic burden is associated with blood DNA methylation changes in individuals with suicidal behavior.

Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Association between mitochondrial DNA and cognitive impairment in schizophrenia: study protocol for a Mexican population.

BACKGROUND: Circulating cell-free mitochondrial DNA (cf-mtDNA) fragments in blood plasma have been reported in patients with schizophrenia (SZ). Although the relationship of cf-mtDNA to the cognitive status of patients with SZ has not yet been explored, it is known that cognitive impairment in SZ compromises the functional and social capacity of these patients and diminishes their quality of life. In this sense, the assessment of the severity of cognitive impairment in a Mexican population with SZ and its association with cf-mtDNA levels in blood plasma may provide the possibility of using cf-mtDNA as a biomarker to determine the status of the disease and the possible ensuing changes over time. METHODS: Subjects for a case-control study will be recruited. cf-mtDNA obtained from blood plasma will be quantified by real-time polymerase chain reaction, using melting curve technology with SYBR green as amplification marker. Patients with SZ will be grouped into those with severe, mild, and no cognitive impairment according to Montreal Cognitive Assessment scale scores, to determine differences between cognitive performance and cf-mtDNA levels in blood plasma. ETHICS AND COMMUNICATION: This study has been approved by the ethics and investigation committees of the High Specialty Regional Hospital of Mental Health (Hospital Regional de Alta Especialidad de Salud Mental); project No. HRAESM/DG/RP/1128/2018. We plan to communicate our research findings in scientific conferences and in peer-reviewed journals. CONCLUSION: It is known that cognitive dysfunction provokes negative effects in an SZ patient´s life. This project aims to provide better knowledge about the role of cf-mtDNA in the pathogenesis of cognitive impairment in SZ, as an attempt to achieve improvements to the existing treatments, thereby helping to prevent major cognitive deterioration.