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

https://doi.org/10.1016/j.pbiomolbio.2020.04.004Get rights and content

Abstract

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.

Introduction

Schizophrenia (SZ) is a chronic and complex mental disorder that affects 1% of the worldwide population (Kaskie et al., 2017). Evidence suggest that males have 30%–40% higher risk of developing SZ than women, and the onset age is between 15 and 24 years in both genders (Moreno-Küstner et al., 2014). The greatest risk factor for developing SZ is having a first-degree relative with the disease (Sullivan, 2005); furthermore, the risk for SZ in an individual whose both parents had been hospitalized due to SZ issues, is four times greater than for an individual with only one parent hospitalized due to SZ issues (Gottesman et al., 2010). SZ is characterized by the presence of positive, negative, or both types of symptoms. Positive symptoms include hallucinations, delusions, and thought disorders. Negative symptoms comprise social withdrawal, self-neglect, loss of motivation and initiative, emotional blunting, and paucity of speech (van Os and Kapur, 2009). Moreover, it is estimated that more than 75% of individual with SZ manifest cognitive impairment, particularly in attention, memory and executive functions (Seidman and Mirsky, 2017). It is known that negative symptoms and cognitive impairments appear since childhood or early adolescence and may precede the first psychotic episode. In this regard, any cognitive impairment in early phases of the disease is characterized as an abnormality in social behavior and academic performance. Interestingly, substance abuse is the most frequent comorbidity in these individuals during their first psychotic episode. Several studies have reported that approximately 80% of individuals with schizophrenia do not achieve a full recovery, estimating a 13.5% remission rate (Charlson et al., 2018). Thus, alterations in cognitive performance cause a negative impact in the quality of life of these individuals and are associated with worse life prognosis (Strassnig et al., 2015).

Section snippets

Pathophysiology of schizophrenia

Several studies have evaluated the imbalanced and depleted interactions of neurotransmitter systems, such as dopaminergic, glutamatergic, GABAergic and serotoninergic, as main hypotheses for the pathophysiology of SZ (Ben-Shachar, 2017). Dopaminergic dysfunction is considered the first pathophysiological mechanism reported in SZ. An increased activity in the mesolimbic pathway through D2, D3, and D4 receptors, would account for the positive symptoms, while a decreased activity in the prefrontal

Mitochondrial dysfunction and mtDNA genetic variants in schizophrenia

Mitochondria are intracellular organelles of eukaryote cells. Their fundamental function is energy production in the form of ATP molecules through OXPHOS. The electron transport is formed by complexes I, II, III, and IV, located in the mitochondrial inner membrane; there, electron transport is catalyzed from reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2) to generate a proton gradient from the mitochondrial matrix to the intermembrane space,

Cell-free mtDNA fragments and schizophrenia

The theories we just discussed suggest an increment of circulating cell-free mtDNA in blood plasma during SZ progression. However, several studies have evaluated the influence of SZ on mtDNA levels and their results contradict each other. For instance, primary scientific evidence postmortem reported no anomalous mtDNA copy number in brain tissues of SZ patients (Sabunciyan et al., 2007; Torrell et al., 2013). Some authors have reported that individuals with SZ exhibit lower mtDNA levels in

Conclusion

In this review, we proposed mtDNA genetic variants as the possible trigger of pathogenic mechanisms in schizophrenia. Moreover, we hypothesized that differences of short-size cell-free mtDNA in plasma levels of individuals with schizophrenia are associated with their cognitive impairment status. Thus, cell-free mtDNA fragments should be used as a biomarker of SZ prognosis and progression, even in the early phases when cognitive impairment begins to be noticeable, in order to prevent

Authors’ contribution

All the authors contributed equally in writing and revising this manuscript, they all provided language assistance, and they all designed and elaborated Fig. 1.

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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