Mfn2在动静脉内瘘血管内膜增生中作用机制的研究进展
Research Progress on the Mechanism of Mfn2 in Vascular Intimal Hyperplasia of Arteriovenous Fistula
摘要: 终末期肾脏病(End-Stage Renal Disease, ESRD)患者大多数选择血液透析治疗。动静脉内瘘(Arteriovenous Fistula, AVF)是血液透析患者最常用的血管通路，但血管内膜增生导致的AVF功能障碍是临床面临的重大挑战。线粒体融合蛋白2 (Mfn2)为线粒体外膜上的跨膜蛋白，不仅可以调控线粒体本身的融合和分裂，还参与氧化应激反应、细胞增殖、细胞死亡、线粒体内质网连接、内质网应激及线粒体自噬等病理生理过程。研究表明，Mfn2可以通过多种机制抑制血管平滑肌细胞(Vascular Smooth Muscle Cells, VSMCs)增殖。文章通过对Mfn2结构、功能及其在血管内膜增生中的潜在作用机制进行研究，旨在为Mfn2与动静脉内瘘成熟不良及远期狭窄的基础研究及临床应用提供科学参考。
Abstract: The majority of end-stage kidney disease patients choose hemodialysis therapy. The arteriovenous fistula (AVF) is a frequently utilized vascular access method for hemodialysis, but it encounters difficulties related to dysfunction caused by intimal hyperplasia. Mfn2, a transmembrane protein on the outer mitochondrial membrane, plays a crucial role in mitochondrial dynamics and is involved in various physiological and pathological processes such as oxidative stress response, cell proliferation, cell death, mitochondria-endoplasmic reticulum interactions, endoplasmic reticulum stress, and mitophagy. Studies have shown that Mfn2 can impede vascular smooth muscle cell (VSMC) proliferation through diverse mechanisms. This investigation aims to explore the role of Mfn2 in addressing poor maturation and long-term stenosis of arteriovenous fistulas by examining its structure, function, and potential mechanisms in intimal hyperplasia, offering insights for both basic research and clinical applications.
文章引用：张晟榕, 段书众. Mfn2在动静脉内瘘血管内膜增生中作用机制的研究进展[J]. 临床医学进展, 2026, 16(2): 1248-1256. https://doi.org/10.12677/acm.2026.162509

参考文献

[1] Viecelli, A.K., Mori, T.A., Roy-Chaudhury, P., Polkinghorne, K.R., Hawley, C.M., Johnson, D.W., et al. (2018) The Pathogenesis of Hemodialysis Vascular Access Failure and Systemic Therapies for Its Prevention: Optimism Unfulfilled. Seminars in Dialysis, 31, 244-257. [Google Scholar] [CrossRef] [PubMed]
[2] Lok, C.E., Huber, T.S., Orchanian-Cheff, A. and Rajan, D.K. (2024) Arteriovenous Access for Hemodialysis. Journal of the American Medical Association, 331, 1307-1317. [Google Scholar] [CrossRef] [PubMed]
[3] Ma, S., Duan, S., Liu, Y. and Wang, H. (2022) Intimal Hyperplasia of Arteriovenous Fistula. Annals of Vascular Surgery, 85, 444-453. [Google Scholar] [CrossRef] [PubMed]
[4] Zhang, Y., Kong, X., Liang, L. and Xu, D. (2024) Regulation of Vascular Remodeling by Immune Microenvironment after the Establishment of Autologous Arteriovenous Fistula in ESRD Patients. Frontiers in Immunology, 15, Article 1365422. [Google Scholar] [CrossRef] [PubMed]
[5] Tait, S.W.G. and Green, D.R. (2012) Mitochondria and Cell Signalling. Journal of Cell Science, 125, 807-815. [Google Scholar] [CrossRef] [PubMed]
[6] Ryan, J.J., Marsboom, G., Fang, Y., Toth, P.T., Morrow, E., Luo, N., et al. (2013) PGC1α-Mediated Mitofusin-2 Deficiency in Female Rats and Humans with Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine, 187, 865-878. [Google Scholar] [CrossRef] [PubMed]
[7] Feng, S., Gao, L., Zhang, D., Tian, X., Kong, L., Shi, H., et al. (2019) miR-93 Regulates Vascular Smooth Muscle Cell Proliferation, and Neointimal Formation through Targeting Mfn2. International Journal of Biological Sciences, 15, 2615-2626. [Google Scholar] [CrossRef] [PubMed]
[8] Joaquim, M. and Escobar-Henriques, M. (2020) Role of Mitofusins and Mitophagy in Life or Death Decisions. Frontiers in Cell and Developmental Biology, 8, Article 572182. [Google Scholar] [CrossRef] [PubMed]
[9] Shen, Y., Jiang, W.L., Li, X., Cao, A.L., Li, D., Li, S.Z., et al. (2023) Mitochondrial Dynamics in Neurological Diseases: A Narrative Review. Annals of Translational Medicine, 11, Article 264. [Google Scholar] [CrossRef] [PubMed]
[10] Xu, X., Lu, F., Du, S. and Zhang, L. (2024) A Case Report of Peroneal Muscle Atrophy Type 2A2 with Central Nervous System Involvement as Initial Presentation. BMC Pediatrics, 24, Article No. 21. [Google Scholar] [CrossRef] [PubMed]
[11] Haller, O., Gao, S., von der Malsburg, A., Daumke, O. and Kochs, G. (2010) Dynamin-Like MxA GTPase: Structural Insights into Oligomerization and Implications for Antiviral Activity. Journal of Biological Chemistry, 285, 28419-28424. [Google Scholar] [CrossRef] [PubMed]
[12] Han, Y., Liu, D., Cheng, Y., Ji, Q., Liu, M., Zhang, B., et al. (2023) Maintenance of Mitochondrial Homeostasis for Alzheimer’s Disease: Strategies and Challenges. Redox Biology, 63, Article 102734. [Google Scholar] [CrossRef] [PubMed]
[13] Chen, G., Liu, N., Zhou, A., Tang, C., Ma, D. and Tang, J. (2001) The Role of Hypertension-Related Gene in Aortic Vascular Smooth Muscle Cells from Mice and Rats. Chinese Medical Journal, 114, 833-836.
[14] Santel, A., Frank, S., Gaume, B., Herrler, M., Youle, R.J. and Fuller, M.T. (2003) Mitofusin-1 Protein Is a Generally Expressed Mediator of Mitochondrial Fusion in Mammalian Cells. Journal of Cell Science, 116, 2763-2774. [Google Scholar] [CrossRef] [PubMed]
[15] Zorzano, A., Hernández-Alvarez, M.I., Sebastián, D. and Muñoz, J.P. (2015) Mitofusin 2 as a Driver That Controls Energy Metabolism and Insulin Signaling. Antioxidants & Redox Signaling, 22, 1020-1031. [Google Scholar] [CrossRef] [PubMed]
[16] Youle, R.J. and van der Bliek, A.M. (2012) Mitochondrial Fission, Fusion, and Stress. Science, 337, 1062-1065. [Google Scholar] [CrossRef] [PubMed]
[17] Depaoli, M.R., Karsten, F., Madreiter-Sokolowski, C.T., Klec, C., Gottschalk, B., Bischof, H., et al. (2018) Real-Time Imaging of Mitochondrial ATP Dynamics Reveals the Metabolic Setting of Single Cells. Cell Reports, 25, 501-512.e3. [Google Scholar] [CrossRef] [PubMed]
[18] Hu, L., Tang, D., Qi, B., Guo, D., Wang, Y., Geng, J., et al. (2024) Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism. Advanced Science, 11, e2307749. [Google Scholar] [CrossRef] [PubMed]
[19] Chen, K.H., Guo, X., Ma, D., Guo, Y., Li, Q., Yang, D., et al. (2004) Dysregulation of HSG Triggers Vascular Proliferative Disorders. Nature Cell Biology, 6, 872-883. [Google Scholar] [CrossRef] [PubMed]
[20] Bock, F.J. and Tait, S.W.G. (2020) Mitochondria as Multifaceted Regulators of Cell Death. Nature Reviews Molecular Cell Biology, 21, 85-100. [Google Scholar] [CrossRef] [PubMed]
[21] Gall, J.M., Wang, Z., Bonegio, R.G., Havasi, A., Liesa, M., Vemula, P., et al. (2015) Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia. Journal of the American Society of Nephrology, 26, 1092-1102. [Google Scholar] [CrossRef] [PubMed]
[22] Zhang, W., Shu, C., Li, Q., Li, M. and Li, X. (2015) Adiponectin Affects Vascular Smooth Muscle Cell Proliferation and Apoptosis through Modulation of the Mitofusin-2-Mediated Ras-Raf-Erk1/2 Signaling Pathway. Molecular Medicine Reports, 12, 4703-4707. [Google Scholar] [CrossRef] [PubMed]
[23] Guo, Z., Tian, Y., Liu, N., Chen, Y., Chen, X., Yuan, G., et al. (2024) Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights. International Journal of Medical Sciences, 21, 2502-2509. [Google Scholar] [CrossRef] [PubMed]
[24] Suen, D.F., Norris, K.L. and Youle, R.J. (2008) Mitochondrial Dynamics and Apoptosis. Genes & Development, 22, 1577-1590. [Google Scholar] [CrossRef] [PubMed]
[25] Li, J., Dang, X., Franco, A. and Dorn, G.W. (2022) Reciprocal Regulation of Mitofusin 2-Mediated Mitophagy and Mitochondrial Fusion by Different PINK1 Phosphorylation Events. Frontiers in Cell and Developmental Biology, 10, Article 868465. [Google Scholar] [CrossRef] [PubMed]
[26] Lin, S., Schneider, C., Su, A.H., Alexe, G., Root, D.E. and Stegmaier, K. (2024) The UBE2J2/UBE2K-MARCH5 Ubiquitination Machinery Regulates Apoptosis in Response to Venetoclax in Acute Myeloid Leukemia. Leukemia, 38, 652-656. [Google Scholar] [CrossRef] [PubMed]
[27] 韩帅, 胡浩洋, 郑嘉鹏, 等. 薯蓣皂苷元通过MFN2介导的线粒体自噬通路诱导肝癌细胞凋亡[J]. 徐州医科大学学报, 2025, 45(9): 625-631.
[28] Abudureyimu, G., Chen, Y., Tang, S., Dong, H., Wang, L., Wu, Y., et al. (2025) Molecular Mechanism of Mfn2 Alleviating Endoplasmic Reticulum Stress and Inhibiting Apoptosis of Sheep Follicular Granulosa Cells. Yi Chuan, 47, 342-350.
[29] Zhang, J., Guo, J., Yang, N., Huang, Y., Hu, T. and Rao, C. (2022) Endoplasmic Reticulum Stress-Mediated Cell Death in Liver Injury. Cell Death & Disease, 13, Article No. 1051. [Google Scholar] [CrossRef] [PubMed]
[30] Rowland, A.A. and Voeltz, G.K. (2012) Endoplasmic Reticulum-Mitochondria Contacts: Function of the Junction. Nature Reviews Molecular Cell Biology, 13, 607-615. [Google Scholar] [CrossRef] [PubMed]
[31] Chen, W., Ma, M., Song, Y., Hua, Y., Jia, H., Liu, J., et al. (2024) Exercise Attenuates Myocardial Ischemia-Reperfusion Injury by Regulating Endoplasmic Reticulum Stress and Mitophagy through M2 Acetylcholine Receptor. Antioxidants & Redox Signaling, 40, 209-221. [Google Scholar] [CrossRef] [PubMed]
[32] Cao, Y., Chen, Z., Hu, J., Feng, J., Zhu, Z., Fan, Y., et al. (2021) Mfn2 Regulates High Glucose-Induced Mams Dysfunction and Apoptosis in Podocytes via PERK Pathway. Frontiers in Cell and Developmental Biology, 9, Article 769213. [Google Scholar] [CrossRef] [PubMed]
[33] Jiang, Y., Krantz, S., Qin, X., Li, S., Gunasekara, H., Kim, Y., et al. (2022) Caveolin-1 Controls Mitochondrial Damage and ROS Production by Regulating Fission—Fusion Dynamics and Mitophagy. Redox Biology, 52, Article 102304. [Google Scholar] [CrossRef] [PubMed]
[34] Liu, L., Zhang, W., Liu, T., Tan, Y., Chen, C., Zhao, J., et al. (2023) The Physiological Metabolite α-Ketoglutarate Ameliorates Osteoarthritis by Regulating Mitophagy and Oxidative Stress. Redox Biology, 62, Article 102663. [Google Scholar] [CrossRef] [PubMed]
[35] Liu, H., Xiang, H., Zhao, S., Sang, H., Lv, F., Chen, R., et al. (2019) Vildagliptin Improves High Glucose‐Induced Endothelial Mitochondrial Dysfunction via Inhibiting Mitochondrial Fission. Journal of Cellular and Molecular Medicine, 23, 798-810. [Google Scholar] [CrossRef] [PubMed]
[36] Wu, L.H., Chang, H.C., Ting, P.C. and Wang, D.L. (2018) Laminar Shear Stress Promotes Mitochondrial Homeostasis in Endothelial Cells. Journal of Cellular Physiology, 233, 5058-5069. [Google Scholar] [CrossRef] [PubMed]
[37] Peng, W., Cai, G., Xia, Y., Chen, J., Wu, P., Wang, Z., et al. (2019) Mitochondrial Dysfunction in Atherosclerosis. DNA and Cell Biology, 38, 597-606. [Google Scholar] [CrossRef] [PubMed]
[38] Salnikova, D., Orekhova, V., Grechko, A., Starodubova, A., Bezsonov, E., Popkova, T., et al. (2021) Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis. International Journal of Molecular Sciences, 22, Article 8990. [Google Scholar] [CrossRef] [PubMed]
[39] Qu, K., Yan, F., Qin, X., Zhang, K., He, W., Dong, M., et al. (2022) Mitochondrial Dysfunction in Vascular Endothelial Cells and Its Role in Atherosclerosis. Frontiers in Physiology, 13, Article 1084604. [Google Scholar] [CrossRef] [PubMed]
[40] Bu, L., Yuan, H., Xie, L., Guo, M., Liao, D. and Zheng, X. (2023) New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death. International Journal of Molecular Sciences, 24, Article 15160. [Google Scholar] [CrossRef] [PubMed]
[41] Baeza, C., Ribagorda, M., Maya-Lopez, C., Fresno, M., Sanchez-Diaz, T., Pintor-Chocano, A., et al. (2024) NIK Is a Mediator of Inflammation and Intimal Hyperplasia in Endothelial Denudation-Induced Vascular Injury. International Journal of Molecular Sciences, 25, Article 11473. [Google Scholar] [CrossRef] [PubMed]
[42] 20 Years of Nature Reviews Nephrology. Nature Reviews Nephrology, 21, Article 717.
[43] 黄鲲. PlGF通过MFN2调控血管内皮线粒体融合稳定动脉粥样硬化斑块的机制研究[D]: [硕士学位论文]. 重庆: 中国人民解放军海军军医大学, 2024.
[44] Qu, Y., Liu, Z.X., Zheng, X.X., Wu, S.N., An, J.Q., et al. (2025) MFN2-Mediated Decrease in Mitochondria-Associated Endoplasmic Reticulum Membranes Contributes to Sunitinib-Induced Endothelial Dysfunction and Hypertension. Journal of Molecular and Cellular Cardiology, 200, 45-60. [Google Scholar] [CrossRef] [PubMed]
[45] Sun, B., Cao, Q., Meng, M. and Wang, X. (2020) MicroRNA-186-5p Serves as a Diagnostic Biomarker in Atherosclerosis and Regulates Vascular Smooth Muscle Cell Proliferation and Migration. Cellular & Molecular Biology Letters, 25, Article No. 27. [Google Scholar] [CrossRef] [PubMed]
[46] Han, Y., Liu, Y., Yang, C., Gao, C., Guo, X. and Cheng, J. (2020) LncRNA CASC2 Inhibits Hypoxia-Induced Pulmonary Artery Smooth Muscle Cell Proliferation and Migration by Regulating the miR-222/ing5 Axis. Cellular & Molecular Biology Letters, 25, Article No. 21. [Google Scholar] [CrossRef] [PubMed]
[47] Jeong, K., Kim, J.H., Murphy, J.M., Park, H., Kim, S., Rodriguez, Y.A.R., et al. (2019) Nuclear Focal Adhesion Kinase Controls Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia through GATA4-Mediated Cyclin D1 Transcription. Circulation Research, 125, 152-166. [Google Scholar] [CrossRef] [PubMed]
[48] Xin, Y., Li, J., Wu, W. and Liu, X. (2021) Mitofusin-2: A New Mediator of Pathological Cell Proliferation. Frontiers in Cell and Developmental Biology, 9, Article 647631. [Google Scholar] [CrossRef] [PubMed]
[49] Li, Y.E., Sowers, J.R., Hetz, C. and Ren, J. (2022) Cell Death Regulation by MAMs: From Molecular Mechanisms to Therapeutic Implications in Cardiovascular Diseases. Cell Death & Disease, 13, Article No. 504. [Google Scholar] [CrossRef] [PubMed]
[50] Xia, Y., Zhang, X., An, P., Luo, J. and Luo, Y. (2023) Mitochondrial Homeostasis in VSMCs as a Central Hub in Vascular Remodeling. International Journal of Molecular Sciences, 24, Article 3483. [Google Scholar] [CrossRef] [PubMed]
[51] Chatterjee, P., Chakraborty, R., Sizer, A.J., O’Brien, B.J., Xu, P., Hwa, J.M., et al. (2025) SUV39H1 Regulates KLF4 and Chromatin Remodeling in Smooth Muscle Cell Phenotypic Plasticity. Arteriosclerosis, Thrombosis, and Vascular Biology, 45, 2015-2033. [Google Scholar] [CrossRef] [PubMed]
[52] Zhang, W.B., Feng, S.Y., Xiao, Z.X., Qi, Y.F., et al. (2022) Down-Regulating of MFN2 Promotes Vascular Calcification via Regulating RAS-RAF-ERK1/2 Pathway. International Journal of Cardiology, 366, 11-18. [Google Scholar] [CrossRef] [PubMed]
[53] Hinton Jr, A., Claypool, S.M., Neikirk, K., Senoo, N., Wanjalla, C.N., Kirabo, A., et al. (2024) Mitochondrial Structure and Function in Human Heart Failure. Circulation Research, 135, 372-396. [Google Scholar] [CrossRef] [PubMed]
[54] Zhang, X., Xu, X., Lu, L., Wan, X., Qin, Y., Ruan, W., et al. (2021) A New Mfn-2 Related Synthetic Peptide Promotes Vascular Smooth Muscle Cell Apoptosis via Regulating the Mitochondrial Apoptotic Pathway by Inhibiting Akt Signaling. Journal of Translational Medicine, 19, Article No. 395. [Google Scholar] [CrossRef] [PubMed]
[55] Wang, X., Zhu, Z., Jia, H., Lu, X., Zhang, Y., Zhu, Y., et al. (2025) Critical Role of Mitochondrial Dynamics in Chronic Respiratory Diseases and New Therapeutic Directions. Chinese Medical Journal, 138, 1783-1793. [Google Scholar] [CrossRef] [PubMed]
[56] Li, P., Li, Z.M., Zhang, B.S., Zhu, L., et al. (2024) S-Propargyl-Cysteine Promotes the Stability of Atherosclerotic Plaque via Maintaining Vascular Muscle Contractile Phenotype. Frontiers in Cell and Developmental Biology, 11, Article 1291170. [Google Scholar] [CrossRef] [PubMed]
[57] Lu, H., Suo, Z., Lin, J., Cong, Y. and Liu, Z. (2024) Monocyte-Macrophages Modulate Intestinal Homeostasis in Inflammatory Bowel Disease. Biomarker Research, 12, Article No. 76. [Google Scholar] [CrossRef] [PubMed]
[58] Liu, L., Gao, J., Tang, Y., Guo, G. and Gan, H. (2023) Increased Expression of the P2Y 12 Receptor Is Involved in the Failure of Autogenous Arteriovenous Fistula Caused by Stenosis. Renal Failure, 45, Article 2278314. [Google Scholar] [CrossRef] [PubMed]
[59] Colunga Biancatelli, R.M.L., Solopov, P., Gregory, B. and Catravas, J.D. (2020) HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF). International Journal of Molecular Sciences, 21, Article 5286. [Google Scholar] [CrossRef] [PubMed]
[60] Samra, G., Rai, V. and Agrawal, D.K. (2022) Innate and Adaptive Immune Cells Associate with Arteriovenous Fistula Maturation and Failure. Canadian Journal of Physiology and Pharmacology, 100, 716-727. [Google Scholar] [CrossRef] [PubMed]
[61] Du, J., Liang, L., Liu, S., Yang, X., Cao, S., Zhang, H., et al. (2020) Neointimal Hyperplasia in the Inferior Vena Cava of Adenine-Induced Chronic Kidney Disease Rats with Aortocaval Fistulas. Clinical and Experimental Nephrology, 24, 1007-1014. [Google Scholar] [CrossRef] [PubMed]
[62] Gameiro, J. and Ibeas, J. (2020) Factors Affecting Arteriovenous Fistula Dysfunction: A Narrative Review. The Journal of Vascular Access, 21, 134-147. [Google Scholar] [CrossRef] [PubMed]
[63] Matsubara, Y., Kiwan, G., Liu, J., Gonzalez, L., Langford, J., Gao, M., et al. (2021) Inhibition of T-Cells by Cyclosporine a Reduces Macrophage Accumulation to Regulate Venous Adaptive Remodeling and Increase Arteriovenous Fistula Maturation. Arteriosclerosis, Thrombosis, and Vascular Biology, 41, e160-e174. [Google Scholar] [CrossRef] [PubMed]
[64] Ge, Z., Chen, Y., Ma, L., Hu, F. and Xie, L. (2024) Macrophage Polarization and Its Impact on Idiopathic Pulmonary Fibrosis. Frontiers in Immunology, 15, Article 1444964. [Google Scholar] [CrossRef] [PubMed]

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