动力蛋白相关蛋白1（Drp1）在非酒精性脂肪性肝病中的作用

沈海珊; 王数; 冯巩

doi:10.12449/JCH250124

动力蛋白相关蛋白1（Drp1）在非酒精性脂肪性肝病中的作用

DOI: 10.12449/JCH250124

沈海珊^1, , ,,
王数¹,
冯巩²

1.
大连大学附属中山医院内科，辽宁大连 116001
2.
西安医学院全科研究所，西安 710021

基金项目:

2023年陕西省教育厅课题 (23JK0646)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：沈海珊负责设计论文框架，起草论文；王数负责文献检索及修改文章；冯巩负责论文修改，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
沈海珊， 1055173553@qq.com （ORCID： 0009-0000-3101-7831）

计量
- 文章访问数: 218
- HTML全文浏览量: 127
- PDF下载量: 32
- 被引次数: 0
出版历程
- 收稿日期: 2024-04-23
- 录用日期: 2024-06-17
- 出版日期: 2025-01-25

Role of dynamin-related protein 1 in non-alcoholic fatty liver disease

Haishan SHEN^{1
, ,
,},
Shuo WANG¹,
Gong FENG²

1.
Department of Internal Medicine，Affiliated Zhongshan Hospital of Dalian University，Dalian，Liaoning 116001，China
2.
Institute of General Practice，Xi’an Medical University，Xi’an 710021，China

Research funding:

2023 Shaanxi Provincial Education Department Project (23JK0646)

More Information

Corresponding author: SHEN Haishan， 1055173553@qq.com （ORCID： 0009-0000-3101-7831）

摘要

摘要: 线粒体的形态变化和功能与非酒精性脂肪性肝病（NAFLD）的发生发展密切相关。动力蛋白相关蛋白1（Drp1）是决定线粒体分裂的最主要蛋白之一，其活性受到严格控制，根据细胞需要确保线粒体动力学的平衡。Drp1可通过促进内质网小管形成，促进线粒体的相互作用和分裂。Drp1的磷酸化状态及去乙酰化也可影响线粒体的形态变化，从而影响NAFLD的疾病状态。本文阐述了Drp1在NAFLD进展中的作用及机制，为靶向治疗NAFLD提供思路。
- 非酒精性脂肪性肝病 /
- 动力蛋白 /
- 线粒体
Abstract: The morphological changes and functions of mitochondria are closely associated with the development and progression of non-alcoholic fatty liver disease （NAFLD）. Dynamin-related protein 1 （Drp1） is one of the primary proteins determining mitochondrial fission， and its activity is strictly controlled to ensure the balance of mitochondrial dynamics according to cellular needs. Drp1 can enhance mitochondrial interactions and mitochondrial fission by promoting the formation of endoplasmic reticulum tubules， and the phosphorylation state and deacetylation of Drp1 can also affect the morphological changes of mitochondria， thereby affecting the status of NAFLD. This article elaborates on the role and mechanism of action of Drp1 in the progression of NAFLD， in order to provide ideas for targeted therapy for NAFLD.
- Non-alcoholic Fatty Liver Disease /
- Dyneins /
- Mitochondria

HTML全文

图 1 Drp1经过磷酸化可引起线粒体分裂

Figure 1. Drp1 phosphorylation can cause mitochondrial fission

下载: 全尺寸图片幻灯片

参考文献(44)

[1]	WONG VWS, EKSTEDT M, WONG GLH, et al. Changing epidemiology, global trends and implications for outcomes of NAFLD[J]. J Hepatol, 2023, 79( 3): 842- 852. DOI: 10.1016/j.jhep.2023.04.036.
[2]	KOKKORAKIS M, BOUTARI C, HILL MA, et al. Resmetirom, the first approved drug for the management of metabolic dysfunction-associated steatohepatitis: Trials, opportunities, and challenges[J]. Metabolism, 2024, 154: 155835. DOI: 10.1016/j.metabol.2024.155835.
[3]	SHUM M, NGO J, SHIRIHAI OS, et al. Mitochondrial oxidative function in NAFLD: Friend or foe?[J]. Mol Metab, 2021, 50: 101134. DOI: 10.1016/j.molmet.2020.101134.
[4]	WU LW, MO WH, FENG J, et al. Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non-alcoholic fatty liver disease by up-regulating the FGF21/PGC-1α pathway[J]. Br J Pharmacol, 2020, 177( 16): 3760- 3777. DOI: 10.1111/bph.15099.
[5]	PARADIES G, PARADIES V, RUGGIERO FM, et al. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease[J]. World J Gastroenterol, 2014, 20( 39): 14205- 14218. DOI: 10.3748/wjg.v20.i39.14205.
[6]	YU LP, LI YJ, WANG T, et al. In vivo recognition of bioactive substances of Polygonum multiflorum for protecting mitochondria against metabolic dysfunction-associated fatty liver disease[J]. World J Gastroenterol, 2023, 29( 1): 171- 189. DOI: 10.3748/wjg.v29.i1.171.
[7]	di CIAULA A, PASSARELLA S, SHANMUGAM H, et al. Nonalcoholic fatty liver disease(NAFLD). Mitochondria as players and targets of therapies?[J]. Int J Mol Sci, 2021, 22( 10): 5375. DOI: 10.3390/ijms22105375.
[8]	MORIO B, PANTHU B, BASSOT A, et al. Role of mitochondria in liver metabolic health and diseases[J]. Cell Calcium, 2021, 94: 102336. DOI: 10.1016/j.ceca.2020.102336.
[9]	KOLIAKI C, SZENDROEDI J, KAUL K, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis[J]. Cell Metab, 2015, 21( 5): 739- 746. DOI: 10.1016/j.cmet.2015.04.004.
[10]	MANSOURI A, GATTOLLIAT CH, ASSELAH T. Mitochondrial dysfunction and signaling in chronic liver diseases[J]. Gastroenterology, 2018, 155( 3): 629- 647. DOI: 10.1053/j.gastro.2018.06.083.
[11]	IOZZO P, BUCCI M, ROIVAINEN A, et al. Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals[J]. Gastroenterology, 2010, 139( 3): 846- 856. e1- e6. DOI: 10.1053/j.gastro.2010.05.039.
[12]	SUNNY NE, PARKS EJ, BROWNING JD, et al. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease[J]. Cell Metab, 2011, 14( 6): 804- 810. DOI: 10.1016/j.cmet.2011.11.004.
[13]	MCGARRY JD, MANNAERTS GP, FOSTER DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis[J]. J Clin Invest, 1977, 60( 1): 265- 270. DOI: 10.1172/JCI108764.
[14]	SATAPATI S, KUCEJOVA B, DUARTE JAG, et al. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver[J]. J Clin Invest, 2015, 125( 12): 4447- 4462. DOI: 10.1172/JCI82204.
[15]	COGLIATI S, ENRIQUEZ JA, SCORRANO L. Mitochondrial cristae: Where beauty meets functionality[J]. Trends Biochem Sci, 2016, 41( 3): 261- 273. DOI: 10.1016/j.tibs.2016.01.001.
[16]	FORMOSA LE, RYAN MT. Mitochondrial OXPHOS complex assembly lines[J]. Nat Cell Biol, 2018, 20( 5): 511- 513. DOI: 10.1038/s41556-018-0098-z.
[17]	WAI T, LANGER T. Mitochondrial dynamics and metabolic regulation[J]. Trends Endocrinol Metab, 2016, 27( 2): 105- 117. DOI: 10.1016/j.tem.2015.12.001.
[18]	EISNER V, PICARD M, HAJNÓCZKY G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses[J]. Nat Cell Biol, 2018, 20( 7): 755- 765. DOI: 10.1038/s41556-018-0133-0.
[19]	SIMULA L, CAMPANELLA M, CAMPELLO S. Targeting Drp1 and mitochondrial fission for therapeutic immune modulation[J]. Pharmacol Res, 2019, 146: 104317. DOI: 10.1016/j.phrs.2019.104317.
[20]	STRACK S, CRIBBS JT. Allosteric modulation of Drp1 mechanoenzyme assembly and mitochondrial fission by the variable domain[J]. J Biol Chem, 2012, 287( 14): 10990- 11001. DOI: 10.1074/jbc.M112.342105.
[21]	FRÖHLICH C, GRABIGER S, SCHWEFEL D, et al. Structural insights into oligomerization and mitochondrial remodelling of dynamin 1-like protein[J]. EMBO J, 2013, 32( 9): 1280- 1292. DOI: 10.1038/emboj.2013.74.
[22]	KISHIDA H, SUGIO S. Crystal structure of GTPase domain fused with minimal stalks from human dynamin-1-like protein(Dlp1) in complex with several nucleotide analogues[J]. Curr Top Pept Protein Res, 2013, 14: 67- 77.
[23]	RAMACHANDRAN R, SCHMID SL. The dynamin superfamily[J]. Curr Biol, 2018, 28( 8): R411- R416. DOI: 10.1016/j.cub.2017.12.013.
[24]	JOSHI AU, SAW NL, SHAMLOO M, et al. Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer’s disease[J]. Oncotarget, 2017, 9( 5): 6128- 6143. DOI: 10.18632/oncotarget.23640.
[25]	JIN JY, WEI XX, ZHI XL, et al. Drp1-dependent mitochondrial fission in cardiovascular disease[J]. Acta Pharmacol Sin, 2021, 42( 5): 655- 664. DOI: 10.1038/s41401-020-00518-y.
[26]	YU R, LIU T, JIN SB, et al. MIEF1/2 function as adaptors to recruit Drp1 to mitochondria and regulate the association of Drp1 with Mff[J]. Sci Rep, 2017, 7( 1): 880. DOI: 10.1038/s41598-017-00853-x.
[27]	SOUNDARARAJAN R, HERNÁNDEZ-CUERVO H, STEARNS TM, et al. A-kinase anchor protein 1 deficiency causes mitochondrial dysfunction in mouse model of hyperoxia induced acute lung injury[J]. Front Pharmacol, 2022, 13: 980723. DOI: 10.3389/fphar.2022.980723.
[28]	CRIBBS JT, STRACK S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death[J]. EMBO Rep, 2007, 8( 10): 939- 944. DOI: 10.1038/sj.embor.7401062.
[29]	ADACHI Y, KATO T, YAMADA T, et al. Drp1 tubulates the ER in a GTPase-independent manner[J]. Mol Cell, 2020, 80( 4): 621- 632. e 6. DOI: 10.1016/j.molcel.2020.10.013.
[30]	NAVARATNARAJAH T, ANAND R, REICHERT AS, et al. The relevance of mitochondrial morphology for human disease[J]. Int J Biochem Cell Biol, 2021, 134: 105951. DOI: 10.1016/j.biocel.2021.105951.
[31]	WANG LX, ISHIHARA T, IBAYASHI Y, et al. Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration[J]. Diabetologia, 2015, 58( 10): 2371- 2380. DOI: 10.1007/s00125-015-3704-7.
[32]	GALLOWAY CA, LEE H, BROOKES PS, et al. Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease[J]. Am J Physiol Gastrointest Liver Physiol, 2014, 307( 6): G632- G641. DOI: 10.1152/ajpgi.00182.2014.
[33]	HAMMERSCHMIDT P, OSTKOTTE D, NOLTE H, et al. CerS6-derived sphingolipids interact with mff and promote mitochondrial fragmentation in obesity[J]. Cell, 2019, 177( 6): 1536- 1552. e 23. DOI: 10.1016/j.cell.2019.05.008.
[34]	XIA WM, VEERAGANDHAM P, CAO Y, et al. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation[J]. Nat Metab, 2024, 6( 2): 273- 289. DOI: 10.1038/s42255-024-00978-0.
[35]	FRIEDMAN JR, LACKNER LL, WEST M, et al. ER tubules mark sites of mitochondrial division[J]. Science, 2011, 334( 6054): 358- 362. DOI: 10.1126/science.1207385.
[36]	BRAVO-SAGUA R, PARRA V, ORTIZ-SANDOVAL C, et al. Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER-mitochondria communication during the early phase of ER stress[J]. Cell Death Differ, 2019, 26( 7): 1195- 1212. DOI: 10.1038/s41418-018-0197-1.
[37]	STEFFEN J, NGO J, WANG SP, et al. The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR[J]. Mol Metab, 2022, 64: 101566. DOI: 10.1016/j.molmet.2022.101566.
[38]	WANG J, YANG Y, SUN F, et al. ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation[J]. Pharmacol Res, 2023, 187: 106608. DOI: 10.1016/j.phrs.2022.106608.
[39]	HU ZQ, ZHANG HY, WANG YT, et al. Exercise activates Sirt1-mediated Drp1 acetylation and inhibits hepatocyte apoptosis to improve nonalcoholic fatty liver disease[J]. Lipids Health Dis, 2023, 22( 1): 33. DOI: 10.1186/s12944-023-01798-z.
[40]	LEMOS V, DE OLIVEIRA RM, NAIA LA, et al. The NAD⁺-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes[J]. Hum Mol Genet, 2017, 26( 21): 4105- 4117. DOI: 10.1093/hmg/ddx298.
[41]	ZHANG LW, XIE XX, TAO JX, et al. Mystery of bisphenol F-induced nonalcoholic fatty liver disease-like changes: Roles of Drp1-mediated abnormal mitochondrial fission in lipid droplet deposition[J]. Sci Total Environ, 2023, 904: 166831. DOI: 10.1016/j.scitotenv.2023.166831.
[42]	QUAN Y, SHOU DW, YANG SQ, et al. Mdivi1 ameliorates mitochondrial dysfunction in non-alcoholic steatohepatitis by inhibiting JNK/MFF signaling[J]. J Gastroenterol Hepatol, 2023, 38( 12): 2215- 2227. DOI: 10.1111/jgh.16372.
[43]	ZHONG YJ, LI ZM, JIN RY, et al. Diosgenin ameliorated type II diabetes-associated nonalcoholic fatty liver disease through inhibiting de novo lipogenesis and improving fatty acid oxidation and mitochondrial function in rats[J]. Nutrients, 2022, 14( 23): 4994. DOI: 10.3390/nu14234994.
[44]	DU JX, WANG TT, XIAO CY, et al. Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates hepatic steatosis In vitro[J]. Curr Mol Med, 2024, 24( 12): 1506- 1517. DOI: 10.2174/0115665240275594231229121030.