Abstract
Objective
Schizophrenia is a serious mental disorder. Mutations in mitochondrial genes can change energy metabolism. Telomere is a tandem sequence at the end of chromosomes. Shorter telomere length has been shown in schizophrenia. The aim of this study was to determine the relationship between ATPase6 gene mutations and telomere length in schizophrenia patients.
Methods
Blood samples of 34 patients and 34 healthy controls were used. In this study conventional PCR, Sanger sequencing technic and real-time PCR were utilized.
Results
Five different mutations (A8860G, A8836, G8697A, C8676T, and A8701G) in the ATPase6 gene were identified in schizophrenia patients. The most seen mutation was A8860G (94%). Telomere length analysis indicated the relation of ATPase6 gene mutations and telomere length variations (p = 0.001). Patients carrying the A8860G mutation had shorter telomere lengths than patients carrying other mutations. Comparing telomere length between schizophrenia patients and healthy controls revealed that the mean telomere length of schizophrenia patients was shorter than healthy controls (p = 0.006). The demographic analysis demonstrated a significant relationship between marital status and telomere length (p = 0.011). Besides that, the duration of the illness is another factor that impacts telomere length (p = 0.044). There is no significant relation between telomere length and other clinical and demographic characteristics including education status, age, gender, etc.
Conclusion
In conclusion, telomere length and ATPase6 gene mutations have a significant relation. Studies with larger patient populations and investigation of other mitochondrial gene mutations will make the clearer link between telomere length and mitochondrial mutations.
Keywords: ATPase6, Mitochondria, Schizophrenia, Telomere
INTRODUCTION
Schizophrenia is a mental disorder characterized by some serious symptoms, including hallucination, delusions, disorganized speech, cognitive dysfunction, and lack of motivation. Besides the hereditary factors, environmental factors like fetal infection, alcohol use, environmental toxins, drug addiction, maternal malnutrition may cause the development of schizophrenia [1,2]. Each symptom is crucial to single out schizophrenia from other mental disorders. Recent studies have shown that impairment of brain development and neuronal connection may be related to the pathology of schizophrenia [3].
Mitochondria is a crucial organelle for a cell because of its role in cell death. Besides that, mitochondria affect neural activity, synapse function, and morphogenesis [4]. Mitochondrial dysfunction causes impairment of the energy state of cells, which may, in turn, give rise to alterations of myelination, neuronal development, and neural connections [3]. Several studies have suggested a relationship between mitochondrial dysfunction and the increasing risk of schizophrenia [3]. There is a general understanding that adenosine triphosphate (ATP) synthase is an important enzyme for the process of energy production in the cell [5]. In the previous studies, ATPase6 gene encoded in mtDNA were shown to have mutations in different diseases [6]. Transcriptomic, proteomic, and metabolic studies using brain tissues revealed that genes associated with energy metabolism and oxidative stress involved in reactive oxygen species (ROS) showed that 90% differences [7] related to impairment, mitochondrial hypoplasia, and alteration of mitochondrial gene expressions [8,9] in schizophrenia patients when compared with the control group [7]. Alterations of mitochondrial function lead to an increase in ROS levels [10]. Increased ROS levels cause damage to DNA, including telomere regions [11]. Because of having a guanine-rich region, telomere tends to break DNA because of oxidative stress [12].
Telomere is a tandem sequence at the end of mammals’ chromosomes and protects genes from degradation and recombination [13]. In each cell division, the telomere diminishes and when arriving at a critical point of proliferation it is arrested and apoptosis tendency increases [14]. Telomere shortening and decrease in telomerase activity, which were shown in previous studies in chronic stress patients [15], were also shown in patients with mental illness [16] and patients with schizophrenia [17]. Otherwise, smoking [18], aging, stress [15] have been associated with telomere shortening.
Though studies have been expanding, yet there are no approved molecular markers for diagnosing schizophrenia, accurately. Although there is an increasing number of studies investigating schizophrenia, no study has evaluated the association between ATPase6 mutations and telomere length in schizophrenia patients. In this study, we have investigated the potential link between telomere length, ATPase6 mutations, and clinical parameters in schizophrenia patients and the control group.
METHODS
Participants
We recruited 34 healthy volunteers with no psychiatric disorder and 34 patients who had been diagnosed with schizophrenia at Ataturk University Research Hospital Psychiatric Clinic between 2020 and 2021. The range of age of schizophrenia patients and healthy volunteers was 18−70. Participants with other chronic medical conditions (including psychiatric comorbidities and diseases as hypertension, cancer, diabetes, etc.) were excluded because their presence in the study could have led to differences in biological parameters that were being explored. Substance use was excluded. The present study was approved by the local Ethic Committee of Ataturk University School of Medicine (decision no: 55). Patients and/or their relatives and healthy subjects were educated about the aim of this study, and written informed consent was obtained from all the participants. For diagnosis Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) [19], was used by an experienced psychiatrist who worked for this study.
DNA Extraction
DNA isolation were performed of 200 ml peripheral blood using DNeasy Blood & Tissue Kit (Qaigen, Hilsen, Germany) according to manufacturer’s protocol. Genomic DNA concentration was measured at A260/280 ratio via Epoch Spectrophotometer System and Take3 Plate (BioTek, Winooski, VT, USA) then samples were stored at −20°C until polymerase chain reaction (PCR) analysis.
PCR and Sanger Sequencing
Genomic DNA was amplified with ATPase6 primer pair and Ecotaq master mix (Eco-Tech Biotechnology, Erzurum, Turkey). Agarose gel electrophoresis was utilized to determine the 675-bp amplicon of ATPase6 gene. To 25-ml reaction mix, 10-pmol/ml primer and 100-ng/ml gDNA were added. PCR program used in SensoQuest (Labcycler, Göttingen, Germany) was at 94°C for 5 minutes, at 94°C for 1 minute, at 59°C for 1 minute, at 72°C for 1 minute, and at 72°C for 5 minutes and had 35 cycles. Amplified PCR products were used to identify DNA sequence variants via Sanger DNA sequencing. To analyze DNA sequence variants Chromas Lite software and other bioinformatics software were used. Variants were searched on an online website (http://www.mitomap.org/MITOMAP).
Telomere Length Analysis
Quantative real-time polymerase chain reaction (QRT-PCR) was used in order to determine telomere length via SsoAdvanced Universal Green Supermix (Bio-Rad, Hercules, CA, USA) according to the manufacturer’s pro-tocol. PCR reaction consists of a 10 ml master mix, a 250 nM primer, and a 10 ng gDNA. PCR program used in Bio-Rad CFX96 (Bio-Rad) was at 98°C for 2 minutes, at 95°C for 15 seconds, and at 60°C for 30 seconds. 36B4 gene was used as an internal control. All reactions were duplicated. Telomere and 36B4 primer sequences had been published before [20]. The length of telomere was calculated with 2−∆∆Ct method.
Psychiatric Evaluation
For diagnosis, DSM-V [19] was used by an experienced psychiatrist who was involved in this study. Positive and Negative Syndrome Scale (PANSS) [21] is a semi-structured rating scale that consists of thirty items with a seven-point severity range, and it is widely used to assess severity of schizophrenia. Clinical global impressions (CGI) [22] consist of positive, negative, depressive, and cognitive functions used to evaluate the severity of the disease [23]. The Brief Psychiatric Rating Scale (BPRS) is widely used for getting quick evaluation of patients’ conditions during interview for determining the presence and degree of severity of the symptoms in each item [24].
Statistically Analysis
According to the results relation of ATPAase6 gene mutations and telomere length was evaluated statistically. In order to analyze data about ATPase6 gene mutations and telomere length by parametric and nonparametric tests Graphpad Prism 7.04 was utilized. Kolmogorov−Smirnov and Shapiro−Wilk tests were used to test whether partici-pants’ telomere length was normally distributed. Telomere length of patients was evaluated by one-way ANOVA according to mutations type. Relation between clinical parameters and telomere length was analyzed with Kruskal−Wallis and Mann−Whitney Utest. Telomere length differences between patients and healthy control were analyzed with the Mann−Whitney Utest. We estimated the sample according to clinical settings and the will to participate in the study and also we paid attention to take enough participants to make parametric tests in statistical analysis. Results with p < 0.05 value were considered as significant.
RESULTS
Characteristics of Participants
Some demographic information and clinical characteristics of patients have been summarized in Table 1. Mean of patients age was 37 ± 10 (mean ± standard deviation; females 38 ± 10, males 35 ± 12) and age of onset was 29 ± 9. Education status of patients was mainly elementary school degree. Tobacco was used by 38% patients. Alcohol consumption was 3% among patients. Among the patients, the rate of those who have children, have suffered from this disease for more than five years, are married, and have a close relative with a psychiatric disease is 29%. There were 35% patients who had underwent treatment for schizophrenia longer than five years. Mainly three antipsychotics were used among the patients. Percentage of the patients who used aripiprazole was 44%, who used clozapine was 18%, and who used Paliperidone was 26%. Some patients’ information was not accessible.
Table 1.
Characteristics of the patients
| Parameters | Patients, n (%) |
|---|---|
| Sex | |
| Female | 16 (47) |
| Male | 18 (53) |
| Education status | |
| Elementary and high school | 21 (62) |
| University or higher | 6 (18) |
| Unidentified | 7 (20) |
| Using tobacco | |
| Yes | 13 (38) |
| No | 15 (44) |
| Unidentified | 6 (18) |
| Having children | |
| Yes | 10 (29) |
| No | 18 (53) |
| Unidentified | 6 (18) |
| Marital status | |
| Married | 10 (29) |
| Single | 19 (56) |
| Unidentified | 5 (15) |
| Presence of psychiatric disease in relative | |
| Yes | 10 (29) |
| No | 18 (53) |
| Unidentified | 6 (18) |
| Duration of illness (yr) | |
| ≤ 5 | 22 (65) |
| > 5 | 10 (29) |
| Unidentified | 2 (6) |
| Antipsychotic medication | |
| Aripiprazole | 15 (44) |
| Clozapine | 6 (18) |
| Paliperidone | 9 (26) |
| Unidentified | 4 (12) |
| Duration of treatment | |
| ≤ 5 | 16 (47) |
| > 5 | 12 (35) |
| Unidentified | 6 (18) |
Clinical Assessment
All patients were evaluated by clinical assessment tools, such as PANSS [21], CGI [22], and BPRS [24] before and after treatment to evaluate treatment efficiency. Pretreatment and post-treatment of PANSS (p < 0.0001) and BPRS (p < 0.0001) scores were evaluated and were significantly different, but CGI score was not significant. Pretreatment PANSS score was 91.65 ± 16.49 (mean ± standard deviation), meaning high grade of severity and post-treatment was 61.57 ± 14.04. Pretreatment CGI score was 5.565 ± 0.84 and post-treatment CGI score was 5.391 ± 1.9. While BPRS pretreatment score was 43.52 ± 10.76 and then it decreased to 22.24 ± 9.2 after treatment. Relation between telomere length and PANSS, CGI, and BPRS scores was evaluated, but any correlation between telomere length and severity of disease was not found. Relation between mutations and severity of disease was also analyzed. No mutation type was significantly associated with PANSS, CGI, or BPRS scores (p > 0.05).
ATPase6 Mutations in Schizophrenia Patients
To ATPase6 gene, 675 bp amplicon was detected by agarose gel electrophoresis for all patients (Fig. 1). ATPase6 gene mutations of schizophrenia patients were summarized in Table 2. ATPase6 gene of 34 schizophrenia patients was analyzed. In 34 patients’ samples, 5 different mutations (A8860G, A8836, G8697A, C8676T, and A8701G) were detected. ATPase6 mutations were determined in all patients however, the A8860G mutation was the most seen one (94%). In just 3 patients (9%) had two mutations. We analyzed the association of mutations type and patients’ characteristics and found no significant relation (p > 0.05).
Fig. 1.
Agarose gel electrophoresis showing ATPase6 gene PCR products (675 bp) of schizophrenia patients. DNA ladder 50 bp; B, blank not including DNA sample. PCR, polymerase chain reaction.
Table 2.
ATPase6mutations frequencies in schizophrenia patients
| Nucleotide | Codon | Number |
|---|---|---|
| A8860G | T112A | 32 |
| A8836G | M104V | 1 |
| G8697A | M57M | 1 |
| C8676T | I50I | 1 |
| A8701G | T59A | 1 |
| The total number of mutations identified | 36 | |
| The total number of the patients carrying the mutation | 34 | |
| The number of sample examined | 34 | |
Telomere Length of Schizophrenia Patients and Control Group
In the study telomere length of 34 patients and 34 healthy participants were amplified using 36B4 as an internal control. Length of telomere in patients (1.34818 ± 1.329) (mean ± standard deviation) was shorter than healthy control (2.41258 ± 1,395) (p = 0.006) (Fig. 2).
Fig. 2.
Telomere length in patients compared with healthy controls. **Means statically very significant.
In Table 3 telomere length of schizophrenia patients and its relation to demographic information were men-tioned. We grouped patients like in Table 3 according to their 2−∆∆Ct value of telomere length analysis. Assessment of telomere length of men and women showed that women had longer telomere but it is not significant (p > 0.05). Old age is an important factor for telomere length. Comparing men and women younger than 33 years old showed that the telomere of women was longer than those of men (p = 0.047) (data not shown in Table 3). While we were evaluating the education status and telomere length, we separated all patients into two groups as in Table 3. Patients certificated with elementary or high school degrees had longer telomere than patients certificated with university or higher degrees but it is not significant (p > 0.05). Using tobacco had not significant effects on telomere length in our patients however smoking patients had shorter telomere length (p > 0.05). Patients who suffered from schizophrenia for more than 5 years had longer telomere (p = 0.044) (Fig. 3A). Having children had a positive effect on the telomere length of patients but it is not significant. Marriage also had positive effects on telomere length, married patients had longer telomere than single patients (p = 0.011) (Fig. 3B). The presence of psychiatric disease in relative was 29% and 60% of them was first-degree relative but it did not affect telomere length. Patients treated longer than 5 years had longer telomere length than patients treated shorter than 5 years (p > 0.05). Type of antipsychotic medication had no significant effect on telomere length, too (p > 0.05). But patients using aripiprazole had longer telomere when compared with other antipsychotic users.
Table 3.
Telomer length and characteristics of the patients
| Parameters | Telomer length | p value |
|---|---|---|
| Age (yr) | 0.4603 | |
| > 33 | 2.33454 | |
| ≤ 33 | 1.34755 | |
| Sex | 0.2361 | |
| Female | 2.72213 | |
| Male | 1.48866 | |
| Education status | 0.1171 | |
| Elementary and high school | 1.94817 | |
| University or higher | 0.796679 | |
| Using tobacco | 0.1148 | |
| Yes | 1.35879 | |
| No | 2.24947 | |
| Having children | 0.0527 | |
| No | 1.38581 | |
| Yes | 2.49534 | |
| Marital status | 0.0110* | |
| Single | 1.25318 | |
| Married | 2.66945 | |
| Presence of psychiatric disease in relative | 0.8868 | |
| Yes | 2.06568 | |
| No | 1.585 | |
| Duration of illness (yr) | 0.0444* | |
| ≤ 5 | 0.977123 | |
| > 5 | 2.16536 | |
| Antipsychotic medication | 0.2736 | |
| Aripiprazole | 2.33094 | |
| Clozapine | 1.45167 | |
| Paliperidone | 0.853389 | |
| Duration of treatment | 0.8695 | |
| ≤ 5 | 1.65119 | |
| > 5 | 1.87161 |
Values (2−∆∆Ct) are presented as the mean of telomere length.
*p < 0.05 was considered significant statistically.
Fig. 3.
(A) Relation of patients’ telomere length and duration of disease. (B) Relation of patients’ telomere length and marital status. *Means statically significant.
ATPase6 Mutations and Telomere Length in Schizophrenia Patients
There was an association between mutations and telomere length (p = 0.001) (Fig. 4). Telomere length of patients with G8697A mutation was longer compared with patients carrying other mutations. Patients carrying A8860G mutation had the shortest telomere in all patients.
Fig. 4.
Relation of telomere length and ATPase6 gene mutations in schizophrenia patients. **Means statically very significant.
DISCUSSION
Impairment of mitochondrial functions and cellular senescence has a link with telomere shortening [25]. Shortening telomere length detected in schizophrenia is consistent with abnormal aging related to the disease [17]. Investigating brain tissues of schizophrenia patients revealed different energy metabolism, oxidative stress, and mitochondrial gene expression [8,9] in schizophrenia than in control [7]. In the study, we evaluated the relation of telomere length and ATPase6 mutations in 34 Turkish schizophrenia patients. To determine telomere length and ATPase6 mutations, qRT-PCR and Sanger sequencing were used, respectively. Results of the mutation analysis showed that mutation rate of samples was 100%. There was a significant relation with mutation type and telomere length. We approved the studies [26-30] that demonstrated shorter telomere length in patients with schizophrenia than healthy controls. Telomere length of patients who diagnosed more than five years were longer than telomere length of patients diagnosed less than 5 years. Besides, married schizophrenia patients had longer telomere than single patients.
There were several studies investigating mitochondrial DNA variants in schizophrenia patients [31-35] (Table 4). Torrell et al. [36] investigated mitochondrial variants in schizophrenia patients and found no pathogenic mtDNA mutation. They determined two schizophrenia related variants. However the variants did not show any relation with neither phenotypic characteristic of schizophrenia nor mitochondrial function [36]. Bi et al. [32] analyzed schizophrenic families and suggested some mitochondrial mutations confer risk to schizophrenia pathogenesis and contribute to mitochondrial dysfunction. In this study sequencing the ATPase6 gene of 34 schizophrenia patients showed that A8860G mutation was more common than other mutations in our patients. We did not find any relation between mutations type and patient characteristics. Some mutations may not lead to remarkable alterations in patients’ characteristics. The discrepancy of mutations type and patients are other factors determining the difference among studies.
Table 4.
Studies investigating mtDNA variants in patients with schizophrenia in the literature
| Literature | Published mtDNA genes | Number of samples | Number of variants |
|---|---|---|---|
| Bertolin et al. [31], 2011 | ATPase6, COII | 89 | 215 |
| Ueno et al. [35], 2009 | ATPase6 | 93 | 220 |
| Martorell et al. [34], 2006 | ATPase6, ND1-5, CO1-3, CYB | 6 | 50 |
| Ivanova et al. [33], 2021 | ND1-5 | 60 | 480 |
| Bi et al. [32], 2016 | Data not available | 11 | 17 |
The link between schizophrenia and telomere length has been an investigation point for many studies. Some of them suggested a relation of shorter telomere length and schizophrenia [26-30] (Table 5) on the contrary other researchers demonstrated longer telomere length in schizophrenia patients [37-41]. There are conflicting results so it has been still needed to be clearer. Our investigation results showed meaningful differences in the telomere length between schizophrenia and healthy controls. The shorter telomere length of schizophrenic patients may be a result of stress or abnormal aging [17] distinct from the disease itself.
Table 5.
Published studies related with telomere length in schizophrenia
| Literature | Patients’ telomere length | Patients number |
|---|---|---|
| Zhang et al. [37], 2018 | Longer | 1,241 |
| Kota et al. [26], 2015 | Shorter | 71 |
| Rao et al. [27], 2016 | Shorter | 141 |
| Nieratschker et al. [38], 2013 | Longer | 539 |
| van Mierlo et al. [28], 2017 | Shorter | 2 |
| Maurya et al. [39], 2018 | Longer | 154 |
| Galletly et al. [29], 2017 | Shorter | 48 |
| Malaspina et al. [40], 2014 | Longer | 53 |
| Monroy-Jaramillo et al. [30], 2017 | Shorter | 170 |
| Cui et al. [41], 2017 | Longer | 126 |
Mitochondrial changes contribute to telomere shortening since the effects of increasing ROS on telomere DNA [10-12]. Abnormal aging related to schizophrenia [17] may be a result of mitochondrial dysfunction and increasing senescence accompanying telomere shortening [25]. Zhou et al. [42] showed shorter telomere length in patients with mitochondrial mutation than healthy controls. In our study patients with different mitochondrial mutations represented different telomere lengths. Patients with A8860G mutation had shorter telomere than other patients who had other mutations. Telomere length of patients with G8697A mutation was longer than others. Differences between studies may cause from different patient populations or different mutations type that was determined. Relation of mitochondria and telomere has been shown directly or indirectly [10-12,42]. However, this is the first study underlined relation of ATPase6 mutations and telomere length in Turkish schizophrenia patients.
Association of smoking and telomere length was investigated before and telomere shortening and smoking have not had any relation [43]. Balzan et al. [44] studied link of alcohol and cigarette consumption and telomere length among schizophrenia patients and did not find any relation. In line with the study we did not found any significant link between smoking and telomere length however smoking patients had shorter telomere length than others. Smoking was more often among patients than controls which may affect telomere length. Marital status of patients may affect their relation with social environment and may cause change of telomere length. Yen and Lung [45] revealed relation of longer telomere length and marriage. Balzan et al. [44] suggested schizophrenia patients who live alone had shorter telomere length than patients live with family. In harmony with the studies, we found that married patients had longer telomere than single patients. This can be a result of diminishing stress by marriage or increasing social interaction in the family.
In schizophrenia patients’ telomere length is affected by many conditions. A study with chronic schizophrenia and early schizophrenia patients suggested a relation of shorter telomere length and longer disease duration [46]. In our study patients with disease duration more than five years had longer telomere length than patients with shorter disease durations. This discrepancy may cause by the variability of patient population or treatment efficiency that was not mentioned. Treatment of the disease by medication can also cause telomere length alteration. Some researchers pointed that psychotropic medications may have anti-oxidative effects and thus prevent telomere attrition [47,48]. A study including schizophrenia patients treated with different twelve antipsychotics including aripiprazole, olanzapine, clozapine revealed a relation between olanzapine and shorter telomere [30]. Yu et al. [48] suggested patients who had a good response to treatment showed longer telomere length. However, in our study, we did not find significant relation between medication and telomere length but patients using Paliperidone had shorter telomere than telomere of patients using other antipsychotics. To measure telomere length before and after treatment may give more information about effect of medication on telomere length. Besides that, increasing telomere length may have been linked with duration of treatment or response to treatment.
The strength of this study is that we evaluated the ATPase6 mutations in patients and telomere length both in patients and controls. We also evaluated telomere length among the patient group by comparing married and unmarried participants, duration of treatment etc. There were several limitations in the present study. First is that the number of subjects was small. Second limitation is that we could not investigate other mitochondrial mutations including ND1-5, CO1-3, CYB. Furthermore, since there were reluctant patients, we could not reach the targeted number of patients and the characteristics of some patients.
Telomere length and mitochondrial mutations were studied separately earlier, however, their relation was not investigated. This is the first study to reveal the relation between ATPase6 mutation and telomere length in schizophrenia patients. Our results suggested that telomere length and mitochondrial mutations had an association. Telomere length shortening may be a result of ATPase6 gene mutations in schizophrenia or vice versa. Telomere length and/or ATPase6 mutations have become a candidate for the molecular marker to discriminate the schizophrenia. Discre-pancies between studies may be the result of varied subject demographics (e.g., age, gender, and socioeconomic status) [49]. Despite all these alterations, attrition of telomere length and determining of gene mutations may contribute to understanding clinical practices of schizophrenia patients [49]. Using a larger patient population and investigation of other mitochondrial mutations may help to better understand molecular changes in schizophrenia.
Limitations
The low number of participants is the main limitation of our study.
Footnotes
Funding
None.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: Sevgi Karabulut Uzunçakmak, Ebubekir Dirican. Data acquisition: Halil Ozcan, Ugur Takim. Formal analysis: Sevgi Karabulut Uzunçakmak. Writing original draft: Sevgi Karabulut Uzunçakmak. Writing review & editing: Sevgi Karabulut Uzunçakmak, Ebubekir Dirican.
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