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Şizofreni hastalarında CYB mtDNA mutasyonları ve PI3K/AKT/mTOR sinyal yolağındaki genlerin ekspresyon durumu

Year 2022, Volume: 47 Issue: 4, 1695 - 1708, 28.12.2022
https://doi.org/10.17826/cumj.1186118

Abstract

Amaç: Bu çalışma, şizofreni hastalarında sitokrom b (CYB) mitokondriyal DNA (mtDNA) mutasyonlarını taramayı ve PI3K/AKT/mTOR sinyal yolağındaki genlerin mRNA ifadelerini analiz etmeyi amaçlamıştır.
Gereç ve Yöntem: Bu çalışmada 44 şizofreni hastasından ve 41 sağlıklı bireyden DNA (hasta) ve RNA (hasta ve kontrol) izolasyonu için tam kan alındı. CYB mtDNA mutasyonları için örnekler PCR ile amplifiye edildi ve Sanger DNA dizi analiziyle tanımlandı. PIK3CA, AKT1 ve mTOR genlerinin mRNA ekspresyonu için RT-PCR ve 2-∆∆Ct metodu kullanıldı.
Bulgular: Şizofreni hastalarında m.15326 A>G (43/44), m.15452 C>A (5/44), m.15078 A>G (3/44), m.14872 C>T (3/44) ve m.14798 T>C (3/44) en sık rastalanan CYB mtDNA mutasyonlarıydı. İn silico analizler, mutasyonların bir kısmının zararlı, hastalık yapıcı veya benign karakterle ilişkili olduğunu gösterdi. Şizofreni hastalarında PIK3CA, AKT1 ve mTOR genlerinin mRNA ekspresyonu sağlıklı bireylere göre anlamlı derecede yüksekti. PIK3CA ve AKT1 genleri arasında anlamlı orta şiddette pozitif bir korelasyon tespit edildi. Ayrıca ROC analizi ile PIK3CA, AKT1 ve mTOR genlerinin hasta grubunda iyi tanısal güce sahip olduğu belirlendi. ROC analizleri, özellikle PIK3CA'nın şizofreni hastaları için % 80 duyarlılık ve % 63,4 seçicilik ile önemli bir tanı değerine sahip olduğunu gösterdi.
Sonuç: Şizofreni hastalarında hem CYB mtDNA mutasyon sıklığı hem de PIK3CA, AKT1 ve mTOR mRNA ekspresyon düzeyi sağlıklı bireylere göre daha yüksekti. Bu mekanizmaları daha geniş şizofreni popülasyonunda çalışmanın hastalığın tanı, tedavi veya prognozunda değerli olabileceğine inanıyoruz.

References

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  • 2. Alsharif KF, Albrakati A, Al omairi NE, et al. Therapeutic antischizophrenic activity of prodigiosin and selenium co-supplementation against amphetamine hydrochloride-induced behavioural changes and oxidative, inflammatory, and apoptotic challenges in rats. Environ Sci Pollut Res. 2022.
  • 3. Fusar-Poli L, Pries L-K, van Os J, et al. The association between cannabis use and facial emotion recognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study. Eur Neuropsychopharmacol. 2022;63:47–59.
  • 4. Tomasik J, Rahmoune H, Guest PC, Bahn S. Neuroimmune biomarkers in schizophrenia. Schizophr Res. 2016;176(1):3–13.
  • 5. Verge B, Alonso Y, Valero J, Miralles C, Vilella E, Martorell L. Mitochondrial DNA (mtDNA) and schizophrenia. Eur Psychiatry. 2011;26(1):45–56.
  • 6. Ivanova EM, Kandilarova SM, Lukanov TI, Naumova EJ, Akabalieva KV, Milanova VK. NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia. Curr Top Med Chem. 2021;21(11):938–48.
  • 7. Ichikawa T, Arai M, Miyashita M, et al. Schizophrenia: Maternal inheritance and heteroplasmy of mtDNA mutations. Mol Genet Metab. 2012;105(1):103–9.
  • 8. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332(6165):644–6.
  • 9. Ruderman NB, Kapeller R, White MF, Cantley LC. Activation of phosphatidylinositol 3-kinase by insulin. Proc Natl Acad Sci. 1990;87(4):1411–5.
  • 10. Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol. 2019;20(9):515–34.
  • 11. Zhu K, Wu Y, He P, et al. PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer. Cells. 2022;11(16):2508.
  • 12. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Discov. 2005;4(12):988–1004.
  • 13. Yu JSL, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 2016;143(17):3050–60. 14. Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol. 2019;59:36–49.
  • 15. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal Cell Death. Physiol Rev. 2018;98(2):813–80.
  • 16. Mishra R, Barthwal MK, Sondarva G, et al. Glycogen Synthase Kinase-3β Induces Neuronal Cell Death via Direct Phosphorylation of Mixed Lineage Kinase 3. J Biol Chem. 2007;282(42):30393–405.
  • 17. Wang L, Zhou K, Fu Z, et al. Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases. J Mol Neurosci. 2017;61(3):379–84.
  • 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013.
  • 19. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophr Bull. 1987;13(2):261–76.
  • 20. Dirican E, Savrun ŞT, Aydın İE, Gülbay G, Karaman Ü. Analysis of mitochondrial DNA cytochrome‐b ( CYB ) and ATPase‐6 gene mutations in COVID‐19 patients. J Med Virol. 2022;94(7):3138–46.
  • 21. Avcilar T, Kirac D, Ergec D, et al. Investigation of the association between mitochondrial DNA and p53 gene mutations in transitional cell carcinoma of the bladder. Oncol Lett. 2016;12(4):2872–9.
  • 22. Dirican E, Çınar İ. Gossypin’in prostat kanser hücrelerinde MMP-2 ve MMP-9 genleri üzerindeki etkisi. Cukurova Med J. 2022;47(3):1290–5.
  • 23. Grantham R. Amino Acid Difference Formula to Help Explain Protein Evolution. Science (80- ). 1974;185(4154):862–4.
  • 24. Abkevich V. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004;41(7):492–507.
  • 25. Huang G, Osorio D, Guan J, Ji G, Cai JJ. Overdispersed gene expression in schizophrenia. Npj Schizophr. 2020;6(1):9.
  • 26. Das SC, Hjelm BE, Rollins BL, et al. Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder. Transl Psychiatry. 2022;12(1):353.
  • 27. Enriquez-Barreto L, Morales M. The PI3K signaling pathway as a pharmacological target in Autism related disorders and Schizophrenia. Mol Cell Ther. 2016;4(1):2.
  • 28. Gonçalves VF, Giamberardino SN, Crowley JJ, et al. Examining the role of common and rare mitochondrial variants in schizophrenia. PLoS One. 2018;13(1):e0191153.
  • 29. Ivanova EM, Kandilarova SM, Lukanov TI, Naumova EJ, Akabalieva KV, Milanova VK. NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia. Curr Top Med Chem. 2021;21(11):938–48.
  • 30. Bi R, Tang J, Zhang W, et al. Mitochondrial genome variations and functional characterization in Han Chinese families with schizophrenia. Schizophr Res. 2016;171(1–3):200–6.
  • 31. Schulmann A, Ryu E, Goncalves V, et al. Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder. Complex Psychiatry. 2019;5(1):13–27.
  • 32. Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr Opin Cell Biol. 2009;21(2):209–18.
  • 33. Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell. 2000;103(2):211–25.
  • 34. He W, Yuan Q-H, Zhou Q. Histamine H3 receptor antagonist Clobenpropit protects propofol-induced apoptosis of hippocampal neurons through PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2018;22(22):8013–20.
  • 35. Jaworski J. Control of Dendritic Arborization by the Phosphoinositide-3’-Kinase-Akt-Mammalian Target of Rapamycin Pathway. J Neurosci. 2005;25(49):11300–12.
  • 36. Tsimberidou A-M, Skliris A, Valentine A, et al. AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology. Cell Biosci. 2022;12(1):56.
  • 37. Arguello PA, Gogos JA. A signaling pathway AKTing up in schizophrenia. J Clin Invest. 2008.
  • 38. Aubry J-M, Schwald M, Ballmann E, Karege F. Early effects of mood stabilizers on the Akt/GSK-3β signaling pathway and on cell survival and proliferation. Psychopharmacology (Berl). 2009;205(3):419–29.
  • 39. Moretti PN, Ota VK, Gouvea ES, et al. Accessing Gene Expression in Treatment-Resistant Schizophrenia. Mol Neurobiol. 2018;55(8):7000–8.
  • 40. Gu S, Cui F, Yin J, Fang C, Liu L. Altered mRNA expression levels of autophagy- and apoptosis-related genes in the FOXO pathway in schizophrenia patients treated with olanzapine. Neurosci Lett. 2021;746:135669.

CYB mtDNA mutations and expression status of genes in the PI3K/AKT/mTOR signaling pathway in patients with schizophrenia

Year 2022, Volume: 47 Issue: 4, 1695 - 1708, 28.12.2022
https://doi.org/10.17826/cumj.1186118

Abstract

Purpose: This study aimed to screen for cytochrome b (CYB) mitochondrial DNA (mtDNA) mutations and analyze the mRNA expressions of genes in the PI3K/AKT/mTOR signaling pathway in patients with schizophrenia.
Materials and Methods: In this study, whole blood was obtained from 44 schizophrenic patients and 41 healthy individuals for DNA (patients) and RNA (patients and control) isolation. Samples for CYB mtDNA mutations were amplified by PCR and identified by Sanger DNA sequencing. RT-PCR and 2-∆∆Ct method was used for mRNA expression of PIK3CA, AKT1, and mTOR genes.
Results: In schizophrenia patients, m.15326 A>G (43/44), m.15452 C>A (5/44), m.15078 A>G (3/44), m.14872 C> T (3/44) and m.14798 T>C (3/44) was the most common CYB mtDNA mutations. In silico analysis showed that some of the mutations were associated with the harmful, disease-causing or benign character. The mRNA expression of the PIK3CA, AKT1, and mTOR genes in schizophrenia patients was significantly higher than in healthy individuals.There was a significant moderate positive correlation between the PIK3CA and AKT1 genes. In addition, by ROC analysis, PIK3CA, AKT1 and mTOR genes were found to have good diagnostic power in the patient group. ROC analyzes showed that PIK3CA in particular has significant diagnostic value for schizophrenia patients with 80% sensitivity and 63.4% specificity.
Conclusion: Both of CYB mtDNA mutations frequency and PIK3CA, AKT1 and mTOR mRNA expression were higher in schizophrenic patients compared to healthy individuals. We believe that studying these mechanisms in the larger schizophrenia population may be valuable in the diagnosis, treatment, or prognosis of the disease.

References

  • 1. Beeraka NM, Avila-Rodriguez MF, Aliev G. Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia. Mol Neurobiol. 2022;59(4):2472–96.
  • 2. Alsharif KF, Albrakati A, Al omairi NE, et al. Therapeutic antischizophrenic activity of prodigiosin and selenium co-supplementation against amphetamine hydrochloride-induced behavioural changes and oxidative, inflammatory, and apoptotic challenges in rats. Environ Sci Pollut Res. 2022.
  • 3. Fusar-Poli L, Pries L-K, van Os J, et al. The association between cannabis use and facial emotion recognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study. Eur Neuropsychopharmacol. 2022;63:47–59.
  • 4. Tomasik J, Rahmoune H, Guest PC, Bahn S. Neuroimmune biomarkers in schizophrenia. Schizophr Res. 2016;176(1):3–13.
  • 5. Verge B, Alonso Y, Valero J, Miralles C, Vilella E, Martorell L. Mitochondrial DNA (mtDNA) and schizophrenia. Eur Psychiatry. 2011;26(1):45–56.
  • 6. Ivanova EM, Kandilarova SM, Lukanov TI, Naumova EJ, Akabalieva KV, Milanova VK. NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia. Curr Top Med Chem. 2021;21(11):938–48.
  • 7. Ichikawa T, Arai M, Miyashita M, et al. Schizophrenia: Maternal inheritance and heteroplasmy of mtDNA mutations. Mol Genet Metab. 2012;105(1):103–9.
  • 8. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332(6165):644–6.
  • 9. Ruderman NB, Kapeller R, White MF, Cantley LC. Activation of phosphatidylinositol 3-kinase by insulin. Proc Natl Acad Sci. 1990;87(4):1411–5.
  • 10. Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol. 2019;20(9):515–34.
  • 11. Zhu K, Wu Y, He P, et al. PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer. Cells. 2022;11(16):2508.
  • 12. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Discov. 2005;4(12):988–1004.
  • 13. Yu JSL, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 2016;143(17):3050–60. 14. Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol. 2019;59:36–49.
  • 15. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal Cell Death. Physiol Rev. 2018;98(2):813–80.
  • 16. Mishra R, Barthwal MK, Sondarva G, et al. Glycogen Synthase Kinase-3β Induces Neuronal Cell Death via Direct Phosphorylation of Mixed Lineage Kinase 3. J Biol Chem. 2007;282(42):30393–405.
  • 17. Wang L, Zhou K, Fu Z, et al. Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases. J Mol Neurosci. 2017;61(3):379–84.
  • 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013.
  • 19. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophr Bull. 1987;13(2):261–76.
  • 20. Dirican E, Savrun ŞT, Aydın İE, Gülbay G, Karaman Ü. Analysis of mitochondrial DNA cytochrome‐b ( CYB ) and ATPase‐6 gene mutations in COVID‐19 patients. J Med Virol. 2022;94(7):3138–46.
  • 21. Avcilar T, Kirac D, Ergec D, et al. Investigation of the association between mitochondrial DNA and p53 gene mutations in transitional cell carcinoma of the bladder. Oncol Lett. 2016;12(4):2872–9.
  • 22. Dirican E, Çınar İ. Gossypin’in prostat kanser hücrelerinde MMP-2 ve MMP-9 genleri üzerindeki etkisi. Cukurova Med J. 2022;47(3):1290–5.
  • 23. Grantham R. Amino Acid Difference Formula to Help Explain Protein Evolution. Science (80- ). 1974;185(4154):862–4.
  • 24. Abkevich V. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004;41(7):492–507.
  • 25. Huang G, Osorio D, Guan J, Ji G, Cai JJ. Overdispersed gene expression in schizophrenia. Npj Schizophr. 2020;6(1):9.
  • 26. Das SC, Hjelm BE, Rollins BL, et al. Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder. Transl Psychiatry. 2022;12(1):353.
  • 27. Enriquez-Barreto L, Morales M. The PI3K signaling pathway as a pharmacological target in Autism related disorders and Schizophrenia. Mol Cell Ther. 2016;4(1):2.
  • 28. Gonçalves VF, Giamberardino SN, Crowley JJ, et al. Examining the role of common and rare mitochondrial variants in schizophrenia. PLoS One. 2018;13(1):e0191153.
  • 29. Ivanova EM, Kandilarova SM, Lukanov TI, Naumova EJ, Akabalieva KV, Milanova VK. NGS-based mtDNA Profiling Could Reveal Genetic Alterations in Schizophrenia. Curr Top Med Chem. 2021;21(11):938–48.
  • 30. Bi R, Tang J, Zhang W, et al. Mitochondrial genome variations and functional characterization in Han Chinese families with schizophrenia. Schizophr Res. 2016;171(1–3):200–6.
  • 31. Schulmann A, Ryu E, Goncalves V, et al. Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder. Complex Psychiatry. 2019;5(1):13–27.
  • 32. Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr Opin Cell Biol. 2009;21(2):209–18.
  • 33. Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell. 2000;103(2):211–25.
  • 34. He W, Yuan Q-H, Zhou Q. Histamine H3 receptor antagonist Clobenpropit protects propofol-induced apoptosis of hippocampal neurons through PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2018;22(22):8013–20.
  • 35. Jaworski J. Control of Dendritic Arborization by the Phosphoinositide-3’-Kinase-Akt-Mammalian Target of Rapamycin Pathway. J Neurosci. 2005;25(49):11300–12.
  • 36. Tsimberidou A-M, Skliris A, Valentine A, et al. AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology. Cell Biosci. 2022;12(1):56.
  • 37. Arguello PA, Gogos JA. A signaling pathway AKTing up in schizophrenia. J Clin Invest. 2008.
  • 38. Aubry J-M, Schwald M, Ballmann E, Karege F. Early effects of mood stabilizers on the Akt/GSK-3β signaling pathway and on cell survival and proliferation. Psychopharmacology (Berl). 2009;205(3):419–29.
  • 39. Moretti PN, Ota VK, Gouvea ES, et al. Accessing Gene Expression in Treatment-Resistant Schizophrenia. Mol Neurobiol. 2018;55(8):7000–8.
  • 40. Gu S, Cui F, Yin J, Fang C, Liu L. Altered mRNA expression levels of autophagy- and apoptosis-related genes in the FOXO pathway in schizophrenia patients treated with olanzapine. Neurosci Lett. 2021;746:135669.
There are 39 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Research
Authors

Ebubekir Dirican 0000-0001-9260-5223

Sevgi Karabulut Uzunçakmak 0000-0001-9714-0349

Halil Özcan 0000-0001-7412-7774

Publication Date December 28, 2022
Acceptance Date December 10, 2022
Published in Issue Year 2022 Volume: 47 Issue: 4

Cite

MLA Dirican, Ebubekir et al. “Şizofreni hastalarında CYB MtDNA Mutasyonları Ve PI3K/AKT/MTOR Sinyal yolağındaki Genlerin Ekspresyon Durumu”. Cukurova Medical Journal, vol. 47, no. 4, 2022, pp. 1695-08, doi:10.17826/cumj.1186118.