酒精干预CyPD的表达影响mPTP所致心肌损伤机制
Mechanism of Alcohol-Mediated CyPD Regulation in mPTP-Dependent Myocardial Injury
DOI: 10.12677/acm.2025.1551560, PDF,   
作者: 胡 彬：南华大学附属怀化医院，湖南 衡阳；申 强*：湖南医药学院总医院心血管内科，湖南 怀化
关键词: 酒精；mPTP；CyPD；心肌损伤；Alcohol； mPTP； CyPD； Myocardial Injury
摘要: CyPD是构成mPTP的基本组成部分之一，且有一些明确的证据支持CyPD是mPTP的主要调节因子；CyPD仍是唯一被遗传学证明的mPTP开放因子；CyPD的表达增加能够经历多种翻译后修饰，如磷酸化、氧化、乙酰化和硝酰化调控mPTP的打开。mPTP的长期开放能够引起线粒体功能障碍，进而导致心肌损伤，目前已有研究表明酒精能够使线粒体上mPTP上CyPD的表达增加及CyPD mRNA表达增加，但酒精通过何种机制引起线粒体上CyPD的表达增加目前尚不清楚，本文就酒精可能通过哪些机制引起CyPD的表达发生变化做一综述。
Abstract: CyPD is one of the fundamental components of mPTP, and substantial evidence indicates that CyPD serves as the primary regulatory factor of mPTP. Moreover, CyPD remains the only genetically validated factor responsible for the opening of mPTP. Enhanced expression of CyPD undergoes various post-translational modifications, including phosphorylation, oxidation, acetylation, and nitroacylation, which collectively regulate the opening of mPTP. The sustained opening of mPTP can lead to mitochondrial dysfunction, thereby causing myocardial injury. Current research demonstrates that alcohol increases the expression of both CyPD and CyPD mRNA in mPTP on mitochondria; however, the precise mechanism underlying alcohol-induced upregulation of CyPD expression on mitochondria remains elusive. This review aims to explore the potential mechanisms by which alcohol may induce changes in CyPD expression.
文章引用：胡彬, 申强. 酒精干预CyPD的表达影响mPTP所致心肌损伤机制[J]. 临床医学进展, 2025, 15(5): 1807-1813. https://doi.org/10.12677/acm.2025.1551560

参考文献

[1] Readnower, R.D., Hubbard, W.B., Kalimon, O.J., Geddes, J.W. and Sullivan, P.G. (2021) Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology. Cells, 10, Article 199. [Google Scholar] [CrossRef] [PubMed]
[2] Sautchuk, R., Kalicharan, B.H., Escalera-Rivera, K., Jonason, J.H., Porter, G.A., Awad, H.A., et al. (2022) Transcriptional Regulation of Cyclophilin D by BMP/Smad Signaling and Its Role in Osteogenic Differentiation. eLife, 11, e75023. [Google Scholar] [CrossRef] [PubMed]
[3] Georgios, A. and Elizabeth, M. (2020) Cyclophilin D: An Integrator of Mitochondrial Function. Frontiers in Physiology, 11, Article 595. [Google Scholar] [CrossRef] [PubMed]
[4] Wong, C.X., Tu, S.J. and Marcus, G.M. (2023) Alcohol and Arrhythmias. JACC: Clinical Electrophysiology, 9, 266-279. [Google Scholar] [CrossRef] [PubMed]
[5] WHO (2021) Development of an Action Plan to Implement the Global Strategy to Reduce Harmful Use of Alcohol in the Eastern Mediterranean Region. Eastern Mediterranean Health Journal, 27, 1239-1240. [Google Scholar] [CrossRef] [PubMed]
[6] Day, E. and Rudd, J.H.F. (2019) Alcohol Use Disorders and the Heart. Addiction, 114, 1670-1678. [Google Scholar] [CrossRef] [PubMed]
[7] Mogos, M.F., Salemi, J.L., Phillips, S.A. and Piano, M.R. (2019) Contemporary Appraisal of Sex Differences in Prevalence, Correlates, and Outcomes of Alcoholic Cardiomyopathy. Alcohol and Alcoholism, 54, 386-395. [Google Scholar] [CrossRef] [PubMed]
[8] Yusupova, A.O. (2014) Alcoholic Cardiomyopathy: Basic Aspects of Epidemiology, Pathogenesis and Pharmacotherapy. Rational Pharmacotherapy in Cardiology, 10, 651-658. [Google Scholar] [CrossRef] 
[9] Hu, Q., Chen, H., Shen, C., Zhang, B., Weng, X., Sun, X., et al. (2022) Impact and Potential Mechanism of Effects of Chronic Moderate Alcohol Consumption on Cardiac Function in Aldehyde Dehydrogenase 2 Gene Heterozygous Mice. Alcoholism: Clinical and Experimental Research, 46, 707-723. [Google Scholar] [CrossRef] [PubMed]
[10] Belosludtsev, K.N., Dubinin, M.V., Belosludtseva, N.V. and Mironova, G.D. (2019) Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochemistry (Moscow), 84, 593-607. [Google Scholar] [CrossRef] [PubMed]
[11] Fernández-Solà, J. (2020) The Effects of Ethanol on the Heart: Alcoholic Cardiomyopathy. Nutrients, 12, Article 572. [Google Scholar] [CrossRef] [PubMed]
[12] Kent, A.C., El Baradie, K.B.Y. and Hamrick, M.W. (2021) Targeting the Mitochondrial Permeability Transition Pore to Prevent Age‐Associated Cell Damage and Neurodegeneration. Oxidative Medicine and Cellular Longevity, 2021, Article ID: 6626484. [Google Scholar] [CrossRef] [PubMed]
[13] Auger, K.R., Serunian, L.A., Soltoff, S.P., Libby, P. and Cantley, L.C. (1989) PDGF-Dependent Tyrosine Phosphorylation Stimulates Production of Novel Polyphosphoinositides in Intact Cells. Cell, 57, 167-175. [Google Scholar] [CrossRef] [PubMed]
[14] Ruderman, N.B., Kapeller, R., White, M.F. and Cantley, L.C. (1990) Activation of Phosphatidylinositol 3-Kinase by Insulin. Proceedings of the National Academy of Sciences, 87, 1411-1415. [Google Scholar] [CrossRef] [PubMed]
[15] Andjelković, M., Maira, S., Cron, P., Parker, P.J. and Hemmings, B.A. (1999) Domain Swapping Used to Investigate the Mechanism of Protein Kinase B Regulation by 3-Phosphoinositide-Dependent Protein Kinase 1 and Ser473 Kinase. Molecular and Cellular Biology, 19, 5061-5072. [Google Scholar] [CrossRef] [PubMed]
[16] Panwar, V., Singh, A., Bhatt, M., Tonk, R.K., Azizov, S., Raza, A.S., et al. (2023) Multifaceted Role of mTOR (Mammalian Target of Rapamycin) Signaling Pathway in Human Health and Disease. Signal Transduction and Targeted Therapy, 8, Article No. 375. [Google Scholar] [CrossRef] [PubMed]
[17] Ilha, J., do Espírito-Santo, C.C. and de Freitas, G.R. (2018) mTOR Signaling Pathway and Protein Synthesis: From Training to Aging and Muscle Autophagy. In: Xiao, J., Ed., Muscle Atrophy, Springer, 139-151. [Google Scholar] [CrossRef] [PubMed]
[18] Zhang, R., Li, G., Zhang, Q., Tang, Q., Huang, J., Hu, C., et al. (2018) Hirsutine Induces mPTP-Dependent Apoptosis through ROCK1/PTEN/PI3K/GSK3β Pathway in Human Lung Cancer Cells. Cell Death & Disease, 9, Article No. 598. [Google Scholar] [CrossRef] [PubMed]
[19] Sun, Q., Jia, N., Li, X., Yang, J. and Chen, G. (2019) Grape Seed Proanthocyanidins Ameliorate Neuronal Oxidative Damage by Inhibiting GSK-3β-Dependent Mitochondrial Permeability Transition Pore Opening in an Experimental Model of Sporadic Alzheimer’s Disease. Aging, 11, 4107-4124. [Google Scholar] [CrossRef] [PubMed]
[20] Morita, M., Gravel, S., Chénard, V., Sikström, K., Zheng, L., Alain, T., et al. (2013) mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation. Cell Metabolism, 18, 698-711. [Google Scholar] [CrossRef] [PubMed]
[21] Guo, Y., Wu, Y., Huang, T., Huang, D., Zeng, Q., Wang, Z., et al. (2024) Licorice Flavonoid Ameliorates Ethanol-Induced Gastric Ulcer in Rats by Suppressing Apoptosis via PI3K/AKT Signaling Pathway. Journal of Ethnopharmacology, 325, Article 117739. [Google Scholar] [CrossRef] [PubMed]
[22] Fayaz, S., Raj, Y. and Krishnamurthy, R. (2015) CYPD: The Key to the Death Door. CNS & Neurological Disorders-Drug Targets, 14, 654-663. [Google Scholar] [CrossRef] [PubMed]
[23] Park, S.H. and Gye, M.C. (2024) Inhibition of Mitochondrial Cyclophilin D, a Downstream Target of Glycogen Synthase Kinase 3α, Improves Sperm Motility. Reproductive Biology and Endocrinology, 22, Article No. 15. [Google Scholar] [CrossRef] [PubMed]
[24] Wang, R.N., Green, J., Wang, Z., Deng, Y., Qiao, M., Peabody, M., et al. (2014) Bone Morphogenetic Protein (BMP) Signaling in Development and Human Diseases. Genes & Diseases, 1, 87-105. [Google Scholar] [CrossRef] [PubMed]
[25] Gauba, E., Chen, H., Guo, L. and Du, H. (2019) Cyclophilin D Deficiency Attenuates Mitochondrial F1fo ATP Synthase Dysfunction via OSCP in Alzheimer’s Disease. Neurobiology of Disease, 121, 138-147. [Google Scholar] [CrossRef] [PubMed]
[26] Ashe, H., Krakowiak, P., Hasterok, S., Sleppy, R., Roller, D.G. and Gioeli, D. (2021) Role of the Runt‐Related Transcription Factor (RUNX) Family in Prostate Cancer. The FEBS Journal, 288, 6112-6126. [Google Scholar] [CrossRef] [PubMed]
[27] Farina, N.H., Zingiryan, A., Akech, J.A., Callahan, C.J., Lu, H., Stein, J.L., et al. (2016) A MicroRNA/Runx1/Runx2 Network Regulates Prostate Tumor Progression from Onset to Adenocarcinoma in TRAMP Mice. Oncotarget, 7, 70462-70474. [Google Scholar] [CrossRef] [PubMed]
[28] Zhang, H., Pan, Y., Zheng, L., Choe, C., Lindgren, B., Jensen, E.D., et al. (2011) FOXO1 Inhibits Runx2 Transcriptional Activity and Prostate Cancer Cell Migration and Invasion. Cancer Research, 71, 3257-3267. [Google Scholar] [CrossRef] [PubMed]
[29] Bai, Y., Yang, Y., Yan, Y., Zhong, J., Blee, A.M., Pan, Y., et al. (2019) RUNX2 Overexpression and PTEN Haploinsufficiency Cooperate to Promote CXCR7 Expression and Cellular Trafficking, AKT Hyperactivation and Prostate Tumorigenesis. Theranostics, 9, 3459-3475. [Google Scholar] [CrossRef] [PubMed]
[30] Haiyan, F., Hao, T., Fa, J., et al. (2023) CypD Induced ROS Output Promotes Intracranial Aneurysm Formation and Rupture by 8-OHdG/NLRP3/MMP9 Pathway. Redox Biology, 67, Article 102887. [Google Scholar] [CrossRef] [PubMed]
[31] Wang, L., Ma, J., Chen, C., Lin, B., Xie, S., Yang, W., et al. (2024) Isoquercitrin Alleviates Pirarubicin-Induced Cardiotoxicity in vivo and in vitro by Inhibiting Apoptosis through Phlpp1/AKT/Bcl-2 Signaling Pathway. Frontiers in Pharmacology, 15, Article 1315001. [Google Scholar] [CrossRef] [PubMed]
[32] Yang, M., Lu, Y., Piao, W. and Jin, H. (2022) The Translational Regulation in mTOR Pathway. Biomolecules, 12, Article 802. [Google Scholar] [CrossRef] [PubMed]
[33] Paquot, N. (2019) The Metabolism of Alcohol. Revue Medicale de Liege, 74, 265-267.
[34] Li, X., Luo, W., Tang, Y., Wu, J., Zhang, J., Chen, S., et al. (2024) Semaglutide Attenuates Doxorubicin-Induced Cardiotoxicity by Ameliorating BNIP3-Mediated Mitochondrial Dysfunction. Redox Biology, 72, Article 103129. [Google Scholar] [CrossRef] [PubMed]
[35] Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y. and Wei, X. (2019) Targeting PI3K in Cancer: Mechanisms and Advances in Clinical Trials. Molecular Cancer, 18, Article No. 26. [Google Scholar] [CrossRef] [PubMed]
[36] Ghafouri-Fard, S., Khanbabapour Sasi, A., Hussen, B.M., Shoorei, H., Siddiq, A., Taheri, M., et al. (2022) Interplay between PI3K/AKT Pathway and Heart Disorders. Molecular Biology Reports, 49, 9767-9781. [Google Scholar] [CrossRef] [PubMed]
[37] Chen, B., Hung, M., Wang, H., Yeh, L., Pandey, S., Chen, R., et al. (2018) GABA Tea Attenuates Cardiac Apoptosis in Spontaneously Hypertensive Rats (SHR) by Enhancing PI3K/Akt‐Mediated Survival Pathway and Suppressing Bax/Bak Dependent Apoptotic Pathway. Environmental Toxicology, 33, 789-797. [Google Scholar] [CrossRef] [PubMed]
[38] Chen, Y., Sivalingam, K., Shibu, M.A., Peramaiyan, R., Day, C.H., Shen, C., et al. (2019) Protective Effect of Fisetin against Angiotensin II-Induced Apoptosis by Activation of IGF-IR-PI3K-Akt Signaling in H9c2 Cells and Spontaneous Hypertension Rats. Phytomedicine, 57, 1-8. [Google Scholar] [CrossRef] [PubMed]
[39] Liu, M., Li, Z., Liang, B., Li, L., Liu, S., Tan, W., et al. (2018) Hydrogen Sulfide Ameliorates Rat Myocardial Fibrosis Induced by Thyroxine through PI3K/AKT Signaling Pathway. Endocrine Journal, 65, 769-781. [Google Scholar] [CrossRef] [PubMed]
[40] Sánchez-Alegría, K., Flores-León, M., Avila-Muñoz, E., Rodríguez-Corona, N. and Arias, C. (2018) PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions. International Journal of Molecular Sciences, 19, Article 3725. [Google Scholar] [CrossRef] [PubMed]
[41] Altomare, D.A., Lyons, G.E., Mitsuuchi, Y., Cheng, J.Q. and Testa, J.R. (1998) Akt2 mRNA Is Highly Expressed in Embryonic Brown Fat and the AKT2 Kinase Is Activated by Insulin. Oncogene, 16, 2407-2411. [Google Scholar] [CrossRef] [PubMed]
[42] Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. and Bilanges, B. (2010) The Emerging Mechanisms of Isoform-Specific PI3K Signalling. Nature Reviews Molecular Cell Biology, 11, 329-341. [Google Scholar] [CrossRef] [PubMed]
[43] Wang, W., Liu, M., Fu, X., Qi, M., Zhu, F., Fan, F., et al. (2024) Hydroxysafflor Yellow a Ameliorates Alcohol-Induced Liver Injury through PI3K/Akt and Stat3/NF-κB Signaling Pathways. Phytomedicine, 132, Article 155814. [Google Scholar] [CrossRef] [PubMed]

为你推荐