线粒体动力学与肿瘤的研究进展
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摘要
线粒体动力学是指线粒体处在融合(fusion)与裂解(fission)的动态平衡中,线粒体的这种动态变化,可表现为形态上的异质性,在胞质中可呈点状、碎片状、条状或线状等不同形态。线粒体动力学与线粒体的功能有密切联系,如细胞增殖、细胞代谢、细胞迁移等,并受多种化学酶及蛋白质的调控。在肿瘤中存在线粒体动力学的失调,线粒体动力学相关蛋白在肿瘤中表达异常,而且线粒体动力学相关蛋白与患者的预后及生存时间相关。线粒体动力学状态的改变可影响肿瘤的发生、发展及转移,但具体机制尚不明确。
Mitochondrial dynamics refers to the balance of fusion and fission in mitochondrial network,the change of mitochondrial dynamics lead to mitochondrial morphological heterogeneity,can be characterized as punctuated,fragmented or linear,tubular mitochondrial in the cytoplasm.Mitochondrial dynamics is closely associated with mitochondrial function,such as cell proliferation,cell metabolism,cell migration,and it is controlled by a variety of chemical enzymes,protein and cytokines.Accumulative evidence is beginning to reveal the close links between cancers and unbalanced mitochondrial dynamics.The expression of mitochondrial dynamic related proteins is dysregulated in human cancers,which is associated with prognosis and survival rate of patients.Alterations of mitochondrial dynamics influence the cancer progress and metastasis,but its mechanism is still unclear.
Mitochondrial dynamics refers to the balance of fusion and fission in mitochondrial network,the change of mitochondrial dynamics lead to mitochondrial morphological heterogeneity,can be characterized as punctuated,fragmented or linear,tubular mitochondrial in the cytoplasm.Mitochondrial dynamics is closely associated with mitochondrial function,such as cell proliferation,cell metabolism,cell migration,and it is controlled by a variety of chemical enzymes,protein and cytokines.Accumulative evidence is beginning to reveal the close links between cancers and unbalanced mitochondrial dynamics.The expression of mitochondrial dynamic related proteins is dysregulated in human cancers,which is associated with prognosis and survival rate of patients.Alterations of mitochondrial dynamics influence the cancer progress and metastasis,but its mechanism is still unclear.
引文
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[2] PERNAS L,SCORRANO L. Mito-morphosis:mitochondrial fusion,fission,and cristae remodeling as key mediators of cellular function[J].Annu Rev Physiol,2016,78:505-531.
[3] ISHIHARA N,OTERA H,OKA T,et al.Regulation and physiologic functions of gtpases in mitochondrial fusion and fission in mammals[J].Antioxid Redox Signal,2013,19(4):389-399.
[4] CRIBBS JT,STRACK S.Functional characterization of phosphorylation sites in dynamin-related protein 1[J].Methods Enzymol,2009,457:231-253.
[5] CHEN H,DETMER SA,EWALD AJ,et al.Mitofusins mfn1 and mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development[J].J Cell Biol,2003,160(2):189-200.
[6] HOPPINS S,NUNNARI J.Cell biology.Mitochondrial dynamics and apoptosis--the ER connection[J].Science,2012,337(6098):1052-1054.
[7] TAGUCHI N,ISHIHARA N,JOFUKU A,et al.Mitotic phosphorylationofdynamin-relatedgtpaseDrp1participates in mitochondrial fission[J].J Biol Chem,2007,282(15):11521-11529.
[8] MARSBOOM G,TOTH PT,RYAN JJ,et al.Dynaminrelated protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension[J].Circ Res,2012,110(11):1484-1497.
[9] PARK YY,LEE S,KARBOWSKI M,et al.Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1[J].J cell Sci,2010,123(Pt 4):619-626.
[10] ZUNINO R,BRASCHI E,XU L,et al.Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis[J].J Biol Chem,2009,284(26):17783-17795.
[11] CASSIDY-STONE A,CHIPUK JE,INGERMAN E,et al.Chemical inhibition of the mitochondrial division dynaminrevealsitsroleinBax/Bak-dependent mitochondrial outer membrane permeabilization[J].Dev Cell,2008,14(2):193-204.
[12] SONG Z,GHOCHANI M,MCCAFFERY JM,et al.Mitofusins and OPA1mediate sequential steps in mitochondrial membrane fusion[J].Mol Biol Cell,2009,20(15):3525-3532.
[13] HOPPINS S,EDLICH F,CLELAND MM,et al.The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes[J].Mol Cell,2011,41(2):150-160.
[14] KOSHIBA T,DETMER SA,KAISER JT,et al.Structural basis of mitochondrial tethering by mitofusin complexes[J].Science,2004,305(5685):858-862.
[15] TWIG G,ELORZA A,MOLINA AJ,et al.Fission and selective fusion govern mitochondrial segregation and elimination by autophagy[J].EMBO J,2008,27(2):433-446.
[16] SENFT D,RONAI ZA.Regulators of mitochondrial dynamics in cancer[J].Curr Opin Cell Biol,2016,39:43-52.
[17] CHEN Y,DORN GW 2ND.PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria[J].Science,2013,340(6131):471-475.
[18] GEGG ME,COOPER JM,CHAU KY,et al.Mitofusin 1and mitofusin 2 are ubiquitinated in a PINK1/parkindependent manner upon induction of mitophagy[J].Hum Mol Genet,2010,19(24):4861-4870.
[19] LEE JY,KAPUR M,LI M,et al.Mfn1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria[J].J Cell Sci,2014,127(Pt 22):4954-4963.
[20] KARBOWSKI M,LEE YJ,GAUME B,et al.Spatial and temporal association of Bax with mitochondrial fission sites,Drp1,and Mfn2 during apoptosis[J].J Cell Biol,2002,159(6):931-938.
[21] TONDERA D,GRANDEMANGE S,JOURDAIN A,et al.SLP-2 is required for stress-induced mitochondrial hyperfusion[J].EMBO J,2009,28(11):1589-1600.
[22] ANAND R,WAI T,BAKER MJ,et al.The i-AAA protease YMEIL and OMA1 cleave OPA1 to balance mitochondrial fusion and fission[J].J Cell Biol,2014,204(6):919-929.
[23] MISHRA P,CARELLI V, MANFREDI G,et al.Proteolytic cleavage of OPA1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation[J].Cell Metab,2014,19(4):630-641.
[24] DIMAURO S,DAVIDZON G.Mitochondrial DNA and disease[J].Annu Med,2005,37(3):222-232.
[25] SONG M,DORN GW 2ND.Mitoconfusion:noncanonical functioning of dynamism factors in static mitochondria of the heart[J].Cell Metab,2015,21(2):195-205.
[26] RYAN JJ,MARSBOOM G,FANG YH,et al.PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension[J].Am J Respir Crit Care Med,2013,187(8):865-878.
[27] HUANG Q,CAO H,ZHAN L,et al.Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells[J].Cancer Lett,2017,403:108-118.
[28] HUANG Q,ZHAN L,CAO H,et al.Increased mitochondrialfissionpromotesautophagyand hepatocellular carcinoma cell survival through the ROSmodulated coordinated regulation of the NFKB and TP53pathways[J].Autophagy,2016,12(6):999-1014.
[29] HAN XJ,YANG ZJ,JIANG LP,et al.Mitochondrial dynamicsregulateshypoxia-inducedmigrationand antineoplastic activity of cisplatin in breast cancer cells[J].Int J Oncol,2015,46(2):691-700.
[30] VON EYSS B,JAENICKE LA,KORTLEVER RM,et al.A MYC-driven change in mitochondrial dynamics limits YAP/TAZ function in mammary epithelial cells and breast cancer[J].Cancer Cell,2015,28(6):743-757.
[31] ZHAO J,ZHANG J,YU M,et al.Mitochondrial dynamics regulates migration and invasion of breast cancer cells[J].Oncogene,2013,32(40):4814-4824.
[32] REHMAN J,ZHANG HJ,TOTH PT,et al.Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer[J].FASEB J,2012,26(5):2175-2186.
[33] MITRA K, WUNDER C,ROYSAM B,et al.A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase[J].Proc Natl Acad Sci U S A,2009,106(29):11960-11965.
[34] ISHIHARA N,NOMURA M,JOFUKU A,et al.Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice[J].Nat Cell Biol,2009,11(8):958-966.
[35] QIAN W,CHOI S,GIBSON GA,et al.Mitochondrial hyperfusion induced by loss of the fission protein Drp1causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress[J].J Cell Sci,2012,125(Pt 23):5745-5757.
[36] FU L,DONG Q,HE J,et al.SIRT4 inhibits malignancy progression of NSCLCS,through mitochondrial dynamics mediated by the ERK-Drp1 pathway[J].Oncogene,2017,36(19):2724-2736.
[37] KARBOWSKI M,ARNOULT D,CHEN H,et al.Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis[J].J Cell Biol,2004,164(4):493-499.
[38] LEE YJ,JEONG SY,KARBOWSKI M,et al.Roles of the mammalian mitochondrial fission and fusion mediators Fis1,Drp1,and Opa1 in apoptosis[J].Molr Biol Cell,2004,15(11):5001-5011.
[39] KARBOWSKI M,NORRIS KL,CLELAND MM,et al.Role of Bax and Bak in mitochondrial morphogenesis[J].Nature,2006,443(7112):658-662.
[40] RENAULT TT,FLOROS KV,ELKHOLI R,et al.Mitochondrial shape governs Bax-induced membrane permeabilization and apoptosis[J].Mol Cell,2015,57(1):69-82.
[41] JI WK,HATCH AL,MERRILL RA,et al.Actin filaments target the oligomeric maturation of the dynamin gtpase Drp1 to mitochondrial fission sites[J].Elife,2015,4:e11553.
[42] KOROBOVA F,RAMABHADRAN V,HIGGS HN.An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2[J].Science,2013,339(6118):464-467.
[43] WAN YY,ZHANG JF,YANG ZJ,et al.Involvement of Drp1 in hypoxia-induced migration of human glioblastoma U251 cells[J].Oncol Rep,2014,32(2):619-626.
[44] YIN M,LU Q,LIU X,et al.Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ROCK1pathway[J].Biochem Biophys Res Commun,2016,478(2):663-668.
[45] WANG W,WANG Y,LONG J,et al.Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1activation in podocytes and endothelial cells[J].Cell Metab,2012,15(2):186-200.
[46] WARBURG O.On the origin of cancer cells[J].Science,1956,123(3191):309-314.
[47] WESTERMANN B.Bioenergetic role of mitochondrial fusion and fission[J].Biochim Biophys Acta,2012,1817(10):1833-1838.
[48] CHEN H,CHOMYN A,CHAN DC.Disruption of fusion results in mitochondrial heterogeneity and dysfunction[J].J Biol Chem,2005,280(28):26185-26192.
[49] PATTEN DA,WONG J,KHACHO M,et al.OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand[J].EMBO J,2014,33(22):2676-2691.
[50] DIETRICH MO, LIUZW, HORVATHTL.Mitochondrial dynamics controlled by mitofusins regulate AGRP neuronal activity and diet-induced obesity[J].Cell,2013,155(1):188-199.
[51] BUCK MD,O′SULLIVAN D,KLEIN GELTINK RI,et al.Mitochondrial dynamics controls T cell fate through metabolic programming[J].Cell,2016,166(1):63-76.
[52] PLECITA-HLAVATA L,LESSARD M,SANTOROVA J,et al.Mitochondrial oxidative phosphorylation and energetic statusarereflectedbymorphologyof mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy[J].Biochim Biophys Acta,2008,1777(7-8):834-846.
[53] HAGENBUCHNER J,KUZNETSOV AV,OBEXER P,et al.BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery[J].Oncogene,2013,32(40):4748-4757.
[54] KONSTANTAKOU EG,VOUTSINAS GE,VELENTZAS AD,et al.3-BrPA eliminates human bladder cancer cells with highly oncogenic signatures via engagement of specific death programs and perturbation of multiple signaling and metabolic determinants[J].Mol Cancer,2015,14:135.
[55] LOZY F,KARANTZA V.Autophagy and cancer cell metabolism[J].Semin Cell Dev Biol,2012,23(4):395-401.
[56] BIN-UMER MA,MCLAUGHLIN JE,BUTTERLY MS,et al.Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes[J].Proc Natl Acad Sci U S A,2014,111(32):11798-11803.
[57] KURIHARA Y,KANKI T,AOKI Y,et al.Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast[J].J Biol chemistry,2012,287(5):3265-3272.
[58] JOSELIN AP,HEWITT SJ,CALLAGHAN SM,et al.ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons[J].Hum Mol Genet,2012,21(22):4888-4903.
[59] MATSUDA S,NAKANISHI A,MINAMI A,et al.Functions and characteristics of PINK1 and Parkin in cancer[J].Front Biosci(Landmark Ed),2015,20:491-501.
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