线粒体融合蛋白Mfn2在糖尿病肾病中作用的研究进展

摘要/Abstract

摘要： 糖尿病肾病(DN)作为糖尿病的重要并发症之一,线粒体功能障碍是DN发展的核心因素。线粒体融合蛋白-2(Mfn2)是一种定位在线粒体外膜的线粒体融合蛋白,在维持线粒体形态与功能中起重要作用。Mfn2可通过减少氧化应激、内质网应激及自噬等方式抑制线粒体形态及功能异常、挽救细胞凋亡并延缓DN的发生发展,故有可能成为DN治疗的潜在靶点。

关键词: 糖尿病肾病, 线粒体融合蛋白, 线粒体, 氧化应激, 自噬, 凋亡

Abstract: Diabetic nephropathy (DN) is one of the serious complications of diabetes, and mitochondrial dysfunction is a core factor in the development of DN. Mitochondrial fusion protein-2 (Mfn2) is a mitochondrial fusion protein that locates in the outer membrane of the mitochondria and plays an important role in maintaining the structure and function of the mitochondria. Mfn2 can inhibit mitochondrial morphology and dysfunction by reducing oxidative stress, endoplasmic reticulum stress and autophagy, save the cells from damages caused by apoptosis and delay the occurrence and development of DN, so it may become a potential target for DN treatment.

Key words: diabetic nephropathy, mitochondrial fusion protein, mitochondrion, oxidative stress, autophagy, apoptosis

中图分类号:

李梦婕, 柯本, 龙脉, 房向东. 线粒体融合蛋白Mfn2在糖尿病肾病中作用的研究进展[J]. 基础医学与临床, 2021, 41(12): 1823-1827.

LI Meng-jie, KE Ben, LONG Mai, FANG Xiang-dong. Research progress on the role of mitochondrial fusion protein Mfn2 in diabetic nephropathy[J]. Basic & Clinical Medicine, 2021, 41(12): 1823-1827.

参考文献

[1]Huang YM, Xu D, Long J, et al. Spectrum of chronic kidney disease in China: a national study based on hospitalized patients from 2010 to 2015[J].Nephrology (Carlton),2019,24:725-736.
[2]Ni Z, Tao L, Xu XH, et al. Polydatin impairs mitochondria fitness and ameliorates podocyte injury by suppressing Drp1 expression[J]. J Cell Physiol,2017,232:2776-2787.
[3]Zhan X, Yan C, Chen Y, et al. Celastrol antagonizes high glucose-evoked podocyte injury, inflammation and insulin resistance by restoring the HO-1-mediated autophagy pathway[J]. Mol Immunol,2018,104:61-68.
[4]Zhu JY, Fu Y, Richman A, et al. A personalized model of COQ2 nephropathy rescued by the wild-type COQ2 allele or dietary coenzyme Q10 supplementation[J]. J Am Soc Nephrol,2017,28:2607-2617.
[5]Tang WX, Wu WH, Zeng XX, et al. Early protective effect of mitofusion 2 over-expression in STZ-induced diabetic rat kidney[J]. Endocrine,2012,41:236-247.
[6]Munoz JP, Ivanova S, Sanchez-Wandelmer J, et al. Mfn2 modulates the UPR and mitochondrial function via repression of PERK[J]. EMBO J,2013,32:2348-2361.
[7]Ju WK, Shim MS, Kim KY, et al. Inhibition of cAMP/PKA pathway protects optic nerve head astrocytes against oxidative stress by Akt/Bax phosphorylation-mediated Mfn1/2 oligomerization[J]. Oxid Med Cell Longev,2019,2019:8060962.doi:10.1155/201918060962.
[8]Huang X, Zhou X, Hu X, et al. Sequences flanking the transmembrane segments facilitate mitochondrial localiza-tion and membrane fusion by mitofusin[J]. Proc Natl Acad Sci U S A,2017,114:e9863-e9872.
[9]Engelhart EA, Hoppins S. A catalytic domain variant of mitofusin requiring a wildtype paralog for function uncouples mitochondrial outer-membrane tethering and fusion[J]. J Biol Chem,2019,294:8001-8014.
[10]McLelland GL, Goiran T, Yi W, et al. Mfn2 ubiqui-tination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy[J]. eLife,2018,7:e32866.doi:10.7554/eLife.32866.
[11]Zhou Y, Carmona S, Muhammad A, et al. Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model[J]. J Clin Invest,2019,130:1756-1771.
[12]Xue R, Meng Q, Lu D, et al. Mitofusin2 induces cell autophagy of pancreatic cancer through inhibiting the PI3K/Akt/mTOR signaling pathway[J]. Oxid Med Cell Longev,2018,2018:2798070.doi:10.1155/201812798070.
[13]Chen K, Dai H, Yuan J, et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy[J]. Cell Death Dis,2018,9:105.doi:10.1381/s1419-017-0127-8.
[14]Zhan M, Usman IM, Sun L, et al. Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease[J]. J Am Soc Nephrol,2015,26:1304-1321.
[15]Wu S, Zhou F, Zhang Z, et al. Mitochondrial oxidative stress causes mitochondrial fragmentation via differential modulation of mitochondrial fission-fusion proteins[J]. FEBS J,2011,278:941-954.
[16]Li T, Han J, Jia L, et al. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation[J]. Protein Cell,2019,10:583-594.
[17]Hou Y, Shi Y, Han B, et al. The antioxidant peptide SS31 prevents oxidative stress, downregulates CD36 and improves renal function in diabetic nephropathy[J]. Nephrol Dial Transplant,2018,33:1908-1918.
[18]Mi X, Tang W, Chen X, et al. Mitofusin 2 attenuates the histone acetylation at collagen IV promoter in diabetic nephropathy[J]. J Mol Endocrinol,2016,57:233-249.
[19]Ju Y, Su Y, Chen Q, et al. Protective effects of Astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats[J]. Biomed Pharmacother,2019,109:84-92.
[20]Chen YY, Peng XF, Liu GY, et al. Protein arginine methyltranferase-1 induces ER stress and epithelial-mesenchymal transition in renal tubular epithelial cells and contributes to diabetic nephropathy[J].Biochim Biophys Acta Mol Basis Dis,2019,1865:2563-2575.
[21]Xu Z, Zhao YJ, Qian YY, et al. EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress[J].Oncotarget,2017,8:32655-32667.
[22]Liu WJ, Gan Y, Huang WF, et al. Lysosome restoration to activate podocyte autophagy: a new therapeutic strategy for diabetic kidney disease[J]. Cell Death Dis,2019,10:806.doi:10.1381/s41419/019-2002-6.
[23]吴海江, 邓新娜, 史永红, 等. EGFR在高糖诱导下人肾小管上皮细胞凋亡中的作用[J]. 基础医学与临床,2016,36:151-155.
[24]Gall JM, Wang Z, Liesa M, et al. Role of mitofusin 2 in the renal stress response[J]. PLoS One,2012,7:e31074.doi:10.1371/journal.pone.0031074.
[25]Takagi S, Li J, Takagaki Y, et al. Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high-fat diet[J]. J Diabetes Investig,2018,9:1025-1032.