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Pharmacy Information 2025
线粒体自噬在糖尿病及其并发症中的作用研究进展
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Abstract:
糖尿病(Diabetes mellitus, DM)作为一种慢性代谢疾病，其发生与胰岛素抵抗和胰岛β细胞受损密切相关，DM及其并发症严重威胁全球健康。线粒体自噬作为清除受损线粒体的关键机制，在DM及其并发症的病理过程中扮演重要角色。本文系统综述了线粒体自噬的核心调控机制，并深入探讨其通过调控氧化应激、炎症反应及细胞稳态，从而改善糖尿病肾病、视网膜病变、神经病变及心血管并发症的作用机制，为基于线粒体自噬的新型药物开发及糖尿病慢性并发症的防治提供依据。
Diabetes mellitus (DM), a chronic metabolic disorder closely associated with insulin resistance and impairment of pancreatic β-cells, poses significant threats to global health through its associated complications. Mitophagy, as a critical quality control mechanism for eliminating damaged mitochondria, plays a pivotal role in the pathological progression of DM and its complications. This review systematically elucidates the core regulatory mechanisms of mitophagy and comprehensively investigates its therapeutic potential in diabetic kidney disease, retinopathy, neuropathy and cardiovascular complications through modulating oxidative stress, inflammatory responses, and cellular homeostasis. The findings provide theoretical foundations for developing novel mitophagy targeted therapeutic strategies and advancing the clinical management of chronic diabetic complications.
| [1] | Xu, Y., Lu, J., Li, M., Wang, T., Wang, K., Cao, Q., et al. (2024) Diabetes in China Part 1: Epidemiology and Risk Factors. The Lancet Public Health, 9, e1089-e1097. https://doi.org/10.1016/s2468-2667(24)00250-0 |
| [2] | Forbes, J.M. and Thorburn, D.R. (2018) Mitochondrial Dysfunction in Diabetic Kidney Disease. Nature Reviews Nephrology, 14, 291-312. https://doi.org/10.1038/nrneph.2018.9 |
| [3] | Wang, S., Long, H., Hou, L., Feng, B., Ma, Z., Wu, Y., et al. (2023) The Mitophagy Pathway and Its Implications in Human Diseases. Signal Transduction and Targeted Therapy, 8, Article No. 304. https://doi.org/10.1038/s41392-023-01503-7 |
| [4] | Blagov, A.V., Summerhill, V.I., Sukhorukov, V.N., Popov, M.A., Grechko, A.V. and Orekhov, A.N. (2023) Type 1 Diabetes Mellitus: Inflammation, Mitophagy, and Mitochondrial Function. Mitochondrion, 72, 11-21. https://doi.org/10.1016/j.mito.2023.07.002 |
| [5] | Shan, Z., Fa, W.H., Tian, C.R., Yuan, C.S. and Jie, N. (2022) Mitophagy and Mitochondrial Dynamics in Type 2 Diabetes Mellitus Treatment. Aging, 14, 2902-2919. https://doi.org/10.18632/aging.203969 |
| [6] | Narendra, D.P. and Youle, R.J. (2024) The Role of Pink1-Parkin in Mitochondrial Quality Control. Nature Cell Biology, 26, 1639-1651. https://doi.org/10.1038/s41556-024-01513-9 |
| [7] | Nguyen, T.T., Wei, S., Nguyen, T.H., Jo, Y., Zhang, Y., Park, W., et al. (2023) Mitochondria-Associated Programmed Cell Death as a Therapeutic Target for Age-Related Disease. Experimental & Molecular Medicine, 55, 1595-1619. https://doi.org/10.1038/s12276-023-01046-5 |
| [8] | Yuan, Y., Zheng, Y., Zhang, X., Chen, Y., Wu, X., Wu, J., et al. (2017) BNIP3L/NIX-Mediated Mitophagy Protects against Ischemic Brain Injury Independent of Park2. Autophagy, 13, 1754-1766. https://doi.org/10.1080/15548627.2017.1357792 |
| [9] | Marinković, M., Šprung, M. and Novak, I. (2020) Dimerization of Mitophagy Receptor BNIP3L/NIX Is Essential for Recruitment of Autophagic Machinery. Autophagy, 17, 1232-1243. https://doi.org/10.1080/15548627.2020.1755120 |
| [10] | Daido, S., Kanzawa, T., Yamamoto, A., Takeuchi, H., Kondo, Y. and Kondo, S. (2004) Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells. Cancer Research, 64, 4286-4293. https://doi.org/10.1158/0008-5472.can-03-3084 |
| [11] | Liu, L., Feng, D., Chen, G., Chen, M., Zheng, Q., Song, P., et al. (2012) Mitochondrial Outer-Membrane Protein FUNDC1 Mediates Hypoxia-Induced Mitophagy in Mammalian Cells. Nature Cell Biology, 14, 177-185. https://doi.org/10.1038/ncb2422 |
| [12] | Wu, H., Wang, Y., Li, W., Chen, H., Du, L., Liu, D., et al. (2019) Deficiency of Mitophagy Receptor FUNDC1 Impairs Mitochondrial Quality and Aggravates Dietary-Induced Obesity and Metabolic Syndrome. Autophagy, 15, 1882-1898. https://doi.org/10.1080/15548627.2019.1596482 |
| [13] | Zhou, H., Zhu, P., Wang, J., Zhu, H., Ren, J. and Chen, Y. (2018) Pathogenesis of Cardiac Ischemia Reperfusion Injury Is Associated with Ck2α-Disturbed Mitochondrial Homeostasis via Suppression of Fundc1-Related Mitophagy. Cell Death & Differentiation, 25, 1080-1093. https://doi.org/10.1038/s41418-018-0086-7 |
| [14] | Chen, G., Han, Z., Feng, D., Chen, Y., Chen, L., Wu, H., et al. (2014) A Regulatory Signaling Loop Comprising the PGAM5 Phosphatase and CK2 Controls Receptor-Mediated Mitophagy. Molecular Cell, 54, 362-377. https://doi.org/10.1016/j.molcel.2014.02.034 |
| [15] | Zhou, H., Zhu, P., Guo, J., Hu, N., Wang, S., Li, D., et al. (2017) Ripk3 Induces Mitochondrial Apoptosis via Inhibition of FUNDC1 Mitophagy in Cardiac IR Injury. Redox Biology, 13, 498-507. https://doi.org/10.1016/j.redox.2017.07.007 |
| [16] | Wu, S., Lu, Q., Ding, Y., Wu, Y., Qiu, Y., Wang, P., et al. (2019) Hyperglycemia-Driven Inhibition of Amp-Activated Protein Kinase Α2 Induces Diabetic Cardiomyopathy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes in Vivo. Circulation, 139, 1913-1936. https://doi.org/10.1161/circulationaha.118.033552 |
| [17] | Di Rita, A., Peschiaroli, A., D’Acunzo, P., Strobbe, D., Hu, Z., Gruber, J., et al. (2018) HUWE1 E3 Ligase Promotes Pink1/Parkin-Independent Mitophagy by Regulating AMBRA1 Activation via IKKα. Nature Communications, 9, Article No. 3755. https://doi.org/10.1038/s41467-018-05722-3 |
| [18] | Di Rienzo, M., Romagnoli, A., Ciccosanti, F., Refolo, G., Consalvi, V., Arena, G., et al. (2021) AMBRA1 Regulates Mitophagy by Interacting with ATAD3A and Promoting PINK1 Stability. Autophagy, 18, 1752-1762. https://doi.org/10.1080/15548627.2021.1997052 |
| [19] | Di Rita, A., D’Acunzo, P., Simula, L., Campello, S., Strappazzon, F. and Cecconi, F. (2018) Ambra1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells. Frontiers in Cellular Neuroscience, 12, Article 92. https://doi.org/10.3389/fncel.2018.00092 |
| [20] | Strappazzon, F., Di Rita, A., Peschiaroli, A., Leoncini, P.P., Locatelli, F., Melino, G., et al. (2019) HUWE1 Controls MCL1 Stability to Unleash Ambra1-Induced Mitophagy. Cell Death & Differentiation, 27, 1155-1168. https://doi.org/10.1038/s41418-019-0404-8 |
| [21] | Haraguchi, R., Kohara, Y., Matsubayashi, K., Kitazawa, R. and Kitazawa, S. (2020) New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney. ACTA Histochemica et Cytochemica, 53, 21-31. https://doi.org/10.1267/ahc.20008 |
| [22] | Giraud-Billoud M., Fader C.M., Aguero R., et al. (2018) Diabetic Nephropathy, Autophagy and Proximal Tubule Protein Endocytic Transport: A Potentially Harmful Relationship. Bio Cell, 42, 35-40. https://doi.org/10.32604/biocell.2018.07010 |
| [23] | Jiang, X., Xiang, X., Chen, X., He, J., Liu, T., Gan, H., et al. (2020) Inhibition of Soluble Epoxide Hydrolase Attenuates Renal Tubular Mitochondrial Dysfunction and ER Stress by Restoring Autophagic Flux in Diabetic Nephropathy. Cell Death & Disease, 11, Article No. 385. https://doi.org/10.1038/s41419-020-2594-x |
| [24] | Chen, K., Dai, H., Yuan, J., Chen, J., Lin, L., Zhang, W., et al. (2018) Optineurin-Mediated Mitophagy Protects Renal Tubular Epithelial Cells against Accelerated Senescence in Diabetic Nephropathy. Cell Death & Disease, 9, Article No. 105. https://doi.org/10.1038/s41419-017-0127-z |
| [25] | Li, J., Zheng, S., Ma, C., Chen, X., Li, X., Li, S., et al. (2023) Research Progress on Exosomes in Podocyte Injury Associated with Diabetic Kidney Disease. Frontiers in Endocrinology, 14, Article 1129884. https://doi.org/10.3389/fendo.2023.1129884 |
| [26] | Salemkour, Y., Yildiz, D., Dionet, L., Hart, D.C., Verheijden, K.A.T., Saito, R., et al. (2023) Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves Trpc6-Mediated Calpain Activation Impairing Autophagy. Journal of the American Society of Nephrology, 34, 1823-1842. https://doi.org/10.1681/asn.0000000000000212 |
| [27] | Zhang, S., Fan, B., Li, Y.L., Zuo, Z. and Li, G. (2023) Oxidative Stress-Involved Mitophagy of Retinal Pigment Epithelium and Retinal Degenerative Diseases. Cellular and Molecular Neurobiology, 43, 3265-3276. https://doi.org/10.1007/s10571-023-01383-z |
| [28] | Alka, K., Kumar, J. and Kowluru, R.A. (2023) Impaired Mitochondrial Dynamics and Removal of the Damaged Mitochondria in Diabetic Retinopathy. Frontiers in Endocrinology, 14, Article 1160155. https://doi.org/10.3389/fendo.2023.1160155 |
| [29] | Gong, Q., Wang, H., Yu, P., Qian, T. and Xu, X. (2021) Protective or Harmful: The Dual Roles of Autophagy in Diabetic Retinopathy. Frontiers in Medicine, 8, Article 644121. https://doi.org/10.3389/fmed.2021.644121 |
| [30] | Devi, T.S., Yumnamcha, T., Yao, F., Somayajulu, M., Kowluru, R.A. and Singh, L.P. (2019) TXNIP Mediates High Glucose-Induced Mitophagic Flux and Lysosome Enlargement in Human Retinal Pigment Epithelial Cells. Biology Open, 8, bio038521. https://doi.org/10.1242/bio.038521 |
| [31] | Yang, J., Yu, Z., Jiang, Y., Zhang, Z., Tian, Y., Cai, J., et al. (2024) SIRT3 Alleviates Painful Diabetic Neuropathy by Mediating the FoxO3a-PINK1-Parkin Signaling Pathway to Activate Mitophagy. CNS Neuroscience & Therapeutics, 30, e14703. https://doi.org/10.1111/cns.14703 |
| [32] | Chang, L., Wu, Y., Wang, H., Tseng, K., Wang, Y., Lu, Y., et al. (2024) Cilostazol Ameliorates Motor Dysfunction and Schwann Cell Impairment in Streptozotocin-Induced Diabetic Rats. International Journal of Molecular Sciences, 25, Article 7847. https://doi.org/10.3390/ijms25147847 |
| [33] | Khan, I., Preeti, K., Kumar, R., Kumar Khatri, D. and Bala Singh, S. (2023) Piceatannol Promotes Neuroprotection by Inducing Mitophagy and Mitobiogenesis in the Experimental Diabetic Peripheral Neuropathy and Hyperglycemia-Induced Neurotoxicity. International Immunopharmacology, 116, Article 109793. https://doi.org/10.1016/j.intimp.2023.109793 |
| [34] | He, J., Qin, Z., Chen, X., He, W., Li, D., Zhang, L., et al. (2022) HIF-1α Ameliorates Diabetic Neuropathic Pain via Parkin-Mediated Mitophagy in a Mouse Model. BioMed Research International, 2022, Article 5274375. https://doi.org/10.1155/2022/5274375 |
| [35] | Ritchie, R.H. and Abel, E.D. (2020) Basic Mechanisms of Diabetic Heart Disease. Circulation Research, 126, 1501-1525. https://doi.org/10.1161/circresaha.120.315913 |
| [36] | Durga Devi, T., Babu, M., Mäkinen, P., Kaikkonen, M.U., Heinaniemi, M., Laakso, H., et al. (2017) Aggravated Postinfarct Heart Failure in Type 2 Diabetes Is Associated with Impaired Mitophagy and Exaggerated Inflammasome Activation. The American Journal of Pathology, 187, 2659-2673. https://doi.org/10.1016/j.ajpath.2017.08.023 |
| [37] | Yu, W., Gao, B., Li, N., Wang, J., Qiu, C., Zhang, G., et al. (2017) SIRT3 Deficiency Exacerbates Diabetic Cardiac Dysfunction: Role of FoxO3a-Parkin-Mediated Mitophagy. Biochimica et Biophysica Acta—Molecular Basis of Disease, 1863, 1973-1983. https://doi.org/10.1016/j.bbadis.2016.10.021 |
| [38] | Wang, S., Zhao, Z., Fan, Y., Zhang, M., Feng, X., Lin, J., et al. (2019) Mst1 Inhibits SIRT3 Expression and Contributes to Diabetic Cardiomyopathy through Inhibiting Parkin-Dependent Mitophagy. Biochimica et Biophysica Acta—Molecular Basis of Disease, 1865, 1905-1914. https://doi.org/10.1016/j.bbadis.2018.04.009 |
| [39] | Wang, S., Zhao, Z., Feng, X., Cheng, Z., Xiong, Z., Wang, T., et al. (2018) Melatonin Activates Parkin Translocation and Rescues the Impaired Mitophagy Activity of Diabetic Cardiomyopathy through Mst1 Inhibition. Journal of Cellular and Molecular Medicine, 22, 5132-5144. https://doi.org/10.1111/jcmm.13802 |
| [40] | Ren, J., Sun, M., Zhou, H., Ajoolabady, A., Zhou, Y., Tao, J., et al. (2020) FUNDC1 Interacts with FBXL2 to Govern Mitochondrial Integrity and Cardiac Function through an IP3R3-Dependent Manner in Obesity. Science Advances, 6, eabc8561. https://doi.org/10.1126/sciadv.abc8561 |
| [41] | Chen, C., Pan, B., Tsai, P., Chen, F., Yang, W. and Shen, M. (2021) Kansuinine A Ameliorates Atherosclerosis and Human Aortic Endothelial Cell Apoptosis by Inhibiting Reactive Oxygen Species Production and Suppressing IKKβ/IκBα/NF-κB Signaling. International Journal of Molecular Sciences, 22, Article 10309. https://doi.org/10.3390/ijms221910309 |
| [42] | Xi, J., Rong, Y., Zhao, Z., Huang, Y., Wang, P., Luan, H., et al. (2021) Scutellarin Ameliorates High Glucose-Induced Vascular Endothelial Cells Injury by Activating PINK1/Parkin-Mediated Mitophagy. Journal of Ethnopharmacology, 271, Article 113855. https://doi.org/10.1016/j.jep.2021.113855 |
| [43] | Zhang, X., Zhou, H. and Chang, X. (2023) Involvement of Mitochondrial Dynamics and Mitophagy in Diabetic Endothelial Dysfunction and Cardiac Microvascular Injury. Archives of Toxicology, 97, 3023-3035. https://doi.org/10.1007/s00204-023-03599-w |
