王凱,夏中元
線粒體自噬在心肌缺血再灌注損傷中的研究進(jìn)展
王凱1,夏中元1
自噬是指細(xì)胞吞噬自身的蛋白質(zhì)或細(xì)胞器并降解,以實現(xiàn)細(xì)胞本身代謝的需要和某些細(xì)胞器的更新。線粒體自噬是指細(xì)胞通過自噬機(jī)制來清除受損或不需要的線粒體。線粒體是真核生物進(jìn)行能量代謝的重要場所,并且參與細(xì)胞分化、細(xì)胞信息傳遞和細(xì)胞凋亡等過程。近年來研究表明,自噬特別是線粒體自噬被認(rèn)為在缺血性心臟疾病中起著重要作用[1],線粒體自噬具有保護(hù)因心肌缺血引起心肌細(xì)胞死亡的作用[2]。線粒體自噬的調(diào)控機(jī)制錯綜復(fù)雜,但經(jīng)過多年研究發(fā)現(xiàn),其調(diào)節(jié)主要與PTEN誘導(dǎo)假定激酶1(PINK1)/Parkin、BNIP3/NIX、FUNDC1等信號通路明顯相關(guān),本文就線粒體自噬在心肌缺血再灌注損傷中的研究進(jìn)展進(jìn)行綜述,并討論線粒體自噬的調(diào)控機(jī)制。
自噬發(fā)生在細(xì)胞內(nèi)并具有重要的生理功能,如降解異常折疊的蛋白質(zhì)、參與氧化應(yīng)激和缺血再灌注等過程[3-5]。研究表明,在心肌缺血過程中,自噬水平明顯升高[6],通過形成自噬小體,與溶酶體結(jié)合形成自噬溶酶體進(jìn)而降解自噬小體的內(nèi)容物,以實現(xiàn)能量代謝的需要和某些細(xì)胞器的更新。在心肌缺血再灌注階段雷帕霉素靶體蛋白(mTOR)和AMP依賴的蛋白激酶(AMPK)在自噬中起重要作用,AMPK促進(jìn)自噬過程而mTOR抑制自噬過程,使用AMPK激動劑和mTOR抑制劑能通過誘導(dǎo)自噬來保護(hù)缺血后的心肌細(xì)胞[7],肝激酶B1(LKB1)、鈣調(diào)蛋白依賴性蛋白激酶β(CaMKKβ)、轉(zhuǎn)化生長因子β活化的激酶1(TAK1)是AMPK的上游激酶[8,9],在AMP或ADP水平升高或胞漿中鈣離子水平升高等情況下激活A(yù)MPK,活化AMPK負(fù)性調(diào)節(jié)mTOR,可直接或經(jīng)mTOR間接磷酸化ULK1激活自噬[10,11]。此外有研究表明,心肌缺血再灌注過程中會激活過度的自噬,導(dǎo)致細(xì)胞功能障礙和細(xì)胞死亡,抑制心肌缺血再灌注過程中過度的自噬會減輕心肌細(xì)胞壞死[12]。
心肌細(xì)胞中富含線粒體,線粒體與心肌缺血再灌注過程密切相關(guān),缺血再灌注可誘導(dǎo)線粒體自噬的發(fā)生,主要涉及到Parkin和BNIP3的變化。H9c2心肌細(xì)胞經(jīng)缺氧復(fù)氧處理后,線粒體內(nèi)PINK1和Parkin水平下降,自噬水平下降[13],Parkin的缺乏會加劇心臟損傷和減少心肌梗死存活率[14]。在H9c2細(xì)胞中,WDR26(G_β類似蛋白)能夠增加線粒體膜電位從而增加Parkin轉(zhuǎn)移到線粒體,在Parkin 轉(zhuǎn)移到線粒體后,增加線粒體蛋白的泛素化,促進(jìn)自噬[15]。細(xì)胞缺氧時BNIP3表達(dá)升高[16],在心肌缺血再灌注損傷過程中,BNIP3可引起線粒體通透性改變,誘導(dǎo)自噬小體的聚集及溶酶體的消耗,促進(jìn)線粒體自噬的發(fā)生[17]。
線粒體自噬與心肌缺血再灌注損傷密切相關(guān),線粒體自噬的調(diào)控有多條信號同路的參與,目前研究熱點(diǎn)主要集中在PINK1/Parkin、BNIP3/NIX、FUNDC1通路。
3.1 PINK1/Parkin 真核細(xì)胞內(nèi)線粒體自噬調(diào)控機(jī)制是目前線粒體自噬領(lǐng)域的研究熱點(diǎn)。研究發(fā)現(xiàn)細(xì)胞能量和氧代謝紊亂、線粒體膜電位變化、細(xì)胞內(nèi)活性氧增多、Ca2+穩(wěn)態(tài)失衡等,引起線粒體損傷或功能障礙的因素均可以誘導(dǎo)線粒體自噬的發(fā)生。目前研究較深入的調(diào)節(jié)線粒體自噬的途徑是PINK1/Parkin通路,且該信號通路依賴泛素的參與[18]。
3.1.1 PINK1/Parkin介導(dǎo)線粒體自噬過程 PINK1是一種絲氨酸/蘇氨酸蛋白激酶,主要存在于線粒體外膜。Parkin是一種E3泛素酶,主要存在于細(xì)胞漿中。線粒體功能正常時,PINK1通過線粒體膜上的轉(zhuǎn)位酶轉(zhuǎn)移到線粒體內(nèi)膜降解。當(dāng)線粒體受損時,PINK1轉(zhuǎn)運(yùn)受阻,聚集于線粒體外膜。此時PINK1會改變泛素分子,改變的泛素隨后會招募Parkin到線粒體,然后E3泛素鏈接酶被激活,通過泛素化底物以激活線粒體自噬[19]。Lazarou等[20]認(rèn)為聚集在線粒體外膜的PINK1通過招募NDP52(核點(diǎn)蛋白質(zhì)52)與視神經(jīng)病變誘導(dǎo)蛋白(optineurin)可直接激活線粒體自噬過程,而NDP52與optineurin通過招募自噬因子ULK1、DFCP 1和WIPI1來標(biāo)記需要降解的線粒體。
當(dāng)泛素出現(xiàn)在線粒體外膜時將會招募受體蛋白,如NBR1和P62。這些受體蛋白含有UBA(泛素相關(guān))域和LIR(LC3相互作用域)序列,可同時結(jié)合配體到泛素標(biāo)記線粒體和自噬小體,使受損線粒體被自噬泡和自噬小體降解[20]。
3.1.2 PINK1/Parkin介導(dǎo)線粒體自噬過程的調(diào)節(jié) 在PINK1/Parkin介導(dǎo)的線粒體自噬過程中,抗凋亡蛋白Bcl-2相關(guān)分子、促凋亡蛋白BH3相關(guān)分子調(diào)節(jié)Parkin向線粒體轉(zhuǎn)移;泛素特異性蛋白酶(USP)能夠調(diào)節(jié)泛素化過程;P62、組蛋白脫乙酰基輔酶6(HDAC6)、optineurin和NDP52是作為線粒體自噬受體調(diào)節(jié)線粒體自噬過程。
抗凋亡蛋白Bcl-2相關(guān)分子(Bcl-XL,Mcl-1和Bcl-W)以Beclin依賴的方式抑制招募Parkin到線粒體膜[19]。Bcl-XL、Mcl-1和Bcl-W與Parkin直接相互作用,阻止Parkin和PINK1的相互作用,從而阻止線粒體蛋白的泛素化。促凋亡BH3蛋白Puma、Noxa、 Bim和Bad能促進(jìn)Parkin轉(zhuǎn)移到線粒體,通過減少Parkin和上述的Bcl-2相關(guān)分子的相互作用,達(dá)到減少招募Parkin到線粒體的作用[19]。Parkin介導(dǎo)的線粒體外膜蛋白(OMM)泛素化,可以招募泛素和LC3結(jié)合接頭蛋白P62,并誘導(dǎo)線粒體自噬[21]。招募和活化Parkin依賴PINK1的磷酸化,同時也磷酸化單個泛素和泛素鏈[22]。
線粒體膜蛋白去泛素化、USP30和USP15能負(fù)性調(diào)節(jié)Parkin介導(dǎo)的線粒體自噬[23,24]。 具有E3泛素連接酶功能的Parkin和具有去泛素化酶功能的USP30能夠平衡調(diào)節(jié)線粒體自噬過程。線粒體損傷能夠刺激Parkin將lys6,lys11和lys63泛素鏈連接到線粒體上,而USP30能夠通過其去泛素化酶功能移除線粒體上的lys6-和lys11-泛素鏈,利用質(zhì)譜技術(shù),發(fā)現(xiàn)重組USP30會優(yōu)先移除完整線粒體上的lys-6和lys11-泛素鏈,抵消Parkin調(diào)節(jié)的泛素鏈形成過程[23]。然而USP8只能選擇性的去泛素化[25]。PARK2(Parkin)主要以K6偶聯(lián)泛素結(jié)合物的形式存在。PARK2與去泛素化酶USP8相互作用,優(yōu)先清除K6連接物,從而調(diào)節(jié)PARK2的活性和功能,并且K6偶聯(lián)泛素結(jié)合物和USP8介導(dǎo)的去泛素化可以調(diào)節(jié)PARK2[26]。然而,其中一個去泛素化復(fù)合體(Ubp3-Bre5)可抑制線粒體自噬,卻能促進(jìn)其他形式的自噬[27]。
Lee等[28]認(rèn)為,P62和組蛋白脫乙?;o酶6(HDAC6)可能是線粒體自噬的重要受體。根據(jù)Parkin介導(dǎo)的泛素化,P62和HDAC6結(jié)合泛素使得受損的線粒體沿著微管到核周位點(diǎn)降解。Narendra等[29]認(rèn)為,P62不僅對于線粒體自噬具有重要作用,且對于線粒體的聚集是必不可少的。在Parkin介導(dǎo)的線粒體自噬過程中,CHDH(膽堿脫氫酶)可以招募P62和LC3到受損的線粒體,并與P62相互作用刺激線粒體自噬[30]。Lazaou等[20]最近證實,optineurin和NDP52對于線粒體自噬是必需的。海拉細(xì)胞被分別敲除五種不同的自噬受體,包括optineurin、NDP52、P62、TAX1BP和NBR1,接著引入不同的受體研究他們在線粒體自噬中的作用。optineurin和NDP52單個敲除并沒有影響線粒體自噬,然而當(dāng)二者都被敲除的時候?qū)柚咕€粒體的降解,表明optineurin和NDP52是最基本的受體。
3.2 BNIP3/NIX BNIP3和NIX(BNIP3L)是一種同源蛋白,均定位于線粒體,均含有LIR基序,可與LIR結(jié)合作為自噬受體誘導(dǎo)線粒體自噬的發(fā)生。但是,在線粒體自噬過程中BNIP3和NIX的表現(xiàn)略有不同,BNIP3在缺氧期間調(diào)節(jié)線粒體自噬,而NIX調(diào)節(jié)紅細(xì)胞譜系成熟時線粒體的自噬過程[31]。當(dāng)細(xì)胞處于惡劣的環(huán)境下時BNIP3可誘導(dǎo)過度線粒體自噬,導(dǎo)致細(xì)胞死亡,而NIX并不能誘導(dǎo)過度的線粒體自噬[32]。
BNIP3是HIF1α(缺氧誘導(dǎo)因子1α)的靶基因,受缺氧誘導(dǎo)但同時也受RB1-E2F1,TP53,F(xiàn)OXO3,NFKB/NF-κB和其他腫瘤相關(guān)的轉(zhuǎn)錄因子的轉(zhuǎn)錄調(diào)控,線粒體外膜的BNIP3 LIR和自噬體膜上經(jīng)處理過的LC3相互作用促進(jìn)線粒體的自噬[33]。通過與LIR相鄰的絲氨酸殘基磷酸化來調(diào)節(jié)BNIP3介導(dǎo)的線粒體自噬的活性[34]。DCT-1是秀麗隱桿線蟲中與哺乳動物BNIP3和BNIP3L/NIX同源的物質(zhì),能在壓力應(yīng)激下介導(dǎo)線粒體自噬促進(jìn)長壽。DCT-1作用于PINK-1-PDR-1/Parkin途徑的下游,并且其在自噬誘導(dǎo)條件下泛素化以介導(dǎo)清除損傷的線粒體[35]。BNIP3 LIR的17和24位絲氨酸殘基磷酸化能特異性的促進(jìn)LC3B和GATE-16的結(jié)合,17位絲氨酸磷酸化是LC3B和GATE-16結(jié)合的先決條件,而24位絲氨酸的磷酸化進(jìn)一步增加對LC3B和GATE-16的親和力。
與BNIP3類似,NIX(BNIP3L)含有SWxxL LIR基序,其LIR的活性受絲氨酸磷酸化調(diào)節(jié)[36]。NIX的功能是作為一個配體蛋白和招募LC3或者γ-氨基丁酸受體相關(guān)蛋白,通過它的N末端的LIR(LC3相互作用域)來引起線粒體的損傷。Zhang等[37]研究發(fā)現(xiàn),正常情況下BNIP3在紅細(xì)胞系統(tǒng)中并不表達(dá),但在BNIP3L(NIX)敲除的小鼠網(wǎng)織紅細(xì)胞成熟過程中,BNIP3有效促進(jìn)網(wǎng)織紅細(xì)胞內(nèi)線粒體的清除,表明BNIP3和NIX存在功能冗余。
3.3 FUNDC1 定位于線粒體外膜的FUNDC1含有三個跨膜結(jié)構(gòu)域和一個N末端的LIR基序,用于結(jié)合LC3和GABARAP蛋白(γ-氨基丁酸受體相關(guān)蛋白)[38]。在正常情況下FUNDC1能穩(wěn)定存在于線粒體外膜而不介導(dǎo)線粒體自噬的發(fā)生。當(dāng)線粒體受損或功能障礙時,通過抑制SRC激酶,使FUNDC1 LIR的18位酪氨酸和酪蛋白激酶2(CK2)13位絲氨酸去磷酸化激活FUNDC1介導(dǎo)的線粒體自噬[38,39]。FUNDC1的18位酪氨酸磷酸化是線粒體自噬的分子開關(guān)[40]。
在缺氧或者線粒體解偶聯(lián)時,PGAM5使FUNDC1的CK2第13位磷酸化的絲氨酸去磷酸化以激活LC3并結(jié)合[39]。FUNDC1-LC3相互作用受到致癌的SRC1激酶活化的調(diào)節(jié),使得FUNDC1 LIR在18位磷酸化[41]。Bcl-XL拮抗PGAM5介導(dǎo)的FUNDC1的去磷酸化,從而防止LC3結(jié)合[42]。表明在FUNDC1系統(tǒng),抗凋亡信號拮抗線粒體自噬反應(yīng)[36]。此外,F(xiàn)UNDC1通過DNM1L/DRP1(線粒體動力相關(guān)蛋白-1)和OPA1(視神經(jīng)萎縮癥蛋白)協(xié)調(diào)線粒體的分裂或融合以及線粒體自噬。線粒體受到應(yīng)激時,將會導(dǎo)致FUNDC1-OPA1復(fù)合物的分解,同時提高DNM1L招募到線粒體,參與線粒體自噬過程[43]。
Hirota等[44]認(rèn)為,在哺乳動物細(xì)胞中,線粒體自噬主要是通過一條可替代途徑發(fā)生,這條途徑需要絲裂原活化蛋白激酶MAPK1和MAPK14信號通路而并非PINK1/Parkin,但是目前對于該信號通路在線粒體自噬中的研究較少,僅有研究表明MAPK14與酵母中的Hog1同源,并且Hog1參與線粒體自噬過程。所以MAPK1和MAPK14在線粒體自噬過程中的具體機(jī)制有待進(jìn)一步研究。
線粒體自噬與心肌缺血再灌注損傷的發(fā)生和發(fā)展密切相關(guān),同時線粒體自噬受多種因素的調(diào)控,在正常情況下細(xì)胞通過自噬來清除受損或功能障礙的線粒體。但是,當(dāng)線粒體自噬過程受阻或過度的自噬時會導(dǎo)致各種疾病的發(fā)生和發(fā)展。因此,探究心肌缺血再灌注損傷過程中線粒體自噬及其調(diào)控機(jī)制有助于掌握線粒體自噬與心肌缺血再灌注損傷及各種疾病的關(guān)系,為臨床治療提供新的思路。
[1] Sciarretta S,Zhai P,Shao D,et al. Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia Pathophysiological Implications in Obesity and Metabolic Syndrome[J]. CIRCULATION,2012,125(9):1134-66.
[2] Moyzis AG,Sadoshima J,Gustafsson AB. Mending a broken heart: the role of mitophagy in cardioprotection[J]. Am J Physiol Heart Circ Physiol,2015,308(3):H183-92.
[3] Bartolome A,Guillen C,Benito M. Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic beta cell death[J].Autophagy,2012,8(12):1757-68.
[4] Quan W,Hur KY,Lim Y,et al. Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice[J]. Diabetologia,2012,55(2):392-403.
[5] Zeng M,Wei X,Wu Z,et al. Simulated ischemia/reperfusion-induced p65-Beclin 1-dependent autophagic cell death in human umbilical vein endothelial cells[J]. Sci Rep,2016,6:37448.
[6] Gui L,Liu B,Lv G. Hypoxia induces autophagy in cardiomyocytes via a hypoxia-inducible factor 1-dependent mechanism[J]. Exp Ther Med,2016,11(6):2233-9.
[7] Huang L,Dai K,Chen M,et al. The AMPK Agonist PT1 and mTOR Inhibitor 3HOI-BA-01 Protect Cardiomyocytes After Ischemia Through Induction of Autophagy[J]. J Cardiovasc Pharmacol Ther,2016,21(1):70-81.
[8] Dalle Pezze P,Ruf S,Sonntag AG,et al. A systems study reveals concurrent activation of AMPK and mTOR by amino acids[J]. Nat Commun,2016,7(13254).
[9] Hindupur SK,Gonzalez A,Hall MN. The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control[J]. Cold Spring Harb Perspect Biol,2015,7(8):a019141.
[10] Kim J,Kundu M,Viollet B,et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1[J]. Nat Cell Biol,2011,13(2):132-41.
[11] Shang L,Wang X. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation[J]. Autophagy,2011,7(8):924-6.
[12] Liu X,Zhang C,Zhang C,et al. Heat shock protein 70 inhibits cardiomyocyte necroptosis through repressing autophagy in myocardial ischemia/reperfusion injury[J]. In Vitro Cell Dev Biol Anim,2016,52(6):690-8.
[13] Sun L,Zhao M,Yang Y,et al. Acetylcholine Attenuates Hypoxia/Reoxygenation Injury by Inducing Mitophagy Through PINK1/Parkin Signal Pathway in H9c2 Cells[J]. J Cell Physiol,2016,231(5):1171-81.
[14] Kubli DA,Zhang X,Lee Y,et al. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction[J].J Biol Chem,2013,288(2):915-26.
[15] Feng Y,Zhao J,Hou H,et al. WDR26 promotes mitophagy of cardiomyocytes induced by hypoxia through Parkin translocation[J].Acta Biochim Biophys Sin (Shanghai),2016,48(12):1075-84.
[16] Wang X,Ma S,Qi G. Effect of hypoxia-inducible factor 1-alpha on hypoxia/reoxygenation-induced apoptosis in primary neonatal rat cardiomyocytes[J]. Biochem Biophys Res Commun,2012,417(4):1227-34.
[17] Ma X,Godar RJ,Liu H,et al. Enhancing lysosome biogenesis attenuates BNIP3-induced cardiomyocyte death[J]. Autophagy,2012,8(3):297-309.
[18] Reeve AK,Simcox EM,Duchen MR,et al. Mitochondrial Degradation,Autophagy and Neurodegenerative Disease[M]. Springer International Publishing,2016,255-78.
[19] Hollville E,Carroll RG,Cullen SP,et al. Bcl-2 family proteins participate in mitochondrial quality control by regulating Parkin/PINK1-dependent mitophagy[J]. Mol Cell,2014,55(3):451-66.
[20] Lazarou M,Sliter DA,Kane LA,et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy[J]. Nature,2015,524(7565):309-14.
[21] Rakovic A,Shurkewitsch K,Seibler P,et al. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cellderived neurons[J]. J Biol Chem,2013,288(4):2223-37.
[22] Okatsu K,Koyano F,Kimura M,et al. Phosphorylated ubiquitin chain is the genuine Parkin receptor[J]. J Cell Biol,2015,209(1):111-28.
[23] Cunningham CN,Baughman JM,Phu L,et al. USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria[J].Nat Cell Biol,2015,17(2):160-9.
[24] Cornelissen T,Haddad D,Wauters F,et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy[J]. Hum Mol Genet,2014,23(19):5227-42.
[25] Durcan TM,Tang MY,Perusse JR,et al. USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin[J]. EMBO J,2014,33(21):2473-91.
[26] Durcan TM,Fon EA. USP8 and PARK2/parkin-mediated mitophagy[J]. Autophagy,2015,11(2):428-9.
[27] Muller M,Kotter P,Behrendt C,et al. Synthetic quantitative array technology identifies the Ubp3-Bre5 deubiquitinase complex as a negative regulator of mitophagy[J]. Cell Rep,2015,10(7):1215-25.
[28] Lee JY,Nagano Y,Taylor JP,et al. Disease-causing mutations in parkin impair mitochondrial ubiquitination,aggregation,and HDAC6-dependent mitophagy[J]. J Cell Biol,2010,189(4):671-9.
[29] Narendra D,Kane LA,Hauser DN,et al. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both[J]. Autophagy,2010,6(8):1090-106.
[30] Park S,Choi SG,Yoo SM,et al. Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy[J]. Autophagy,2014,10(11):1906-20.
[31] Ney PA. Mitochondrial autophagy: Origins,significance,and role of BNIP3 and NIX[J]. Biochim Biophys Acta,2015,1853(10 Pt B):2775-83.
[32] Shi RY,Zhu SH,Li V,et al. BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke[J]. CNS Neurosci Ther,2014,20(12):1045-55.
[33] Chourasia AH,Macleod KF. Tumor suppressor functions of BNIP3 and mitophagy[J]. Autophagy,2015,11(10):1937-8.
[34] Zhu Y,Massen S,Terenzio M,et al. Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis[J]. J Biol Chem,2013,288(2):1099-113.
[35] Palikaras K,Lionaki E,Tavernarakis N. Coupling mitogenesis and mitophagy for longevity[J]. Autophagy,2015,11(8):1428-30.
[36] Hamacher-Brady A,Brady NR. Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy[J].Cell Mol Life Sci,2016,73(4):775-95.
[37] Zhang J,Loyd MR,Randall MS,et al. A short linear motif in BNIP3L(NIX) mediates mitochondrial clearance in reticulocytes[J].Autophagy, 2012,8(9):1325-32.
[38] Liu L,Feng D,Chen G,et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells[J]. Nat Cell Biol,2012,14(2):177-85.
[39] Chen G,Han Z,Feng D,et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy[J]. Mol Cell,2014,54(3):362-77.
[40] Kuang Y,Ma K,Zhou C,et al. Structural basis for the phosphorylation of FUNDC1 LIR as a molecular switch of mitophagy[J].Autophagy,2016:1-11.
[41] Wu W,Tian W,Hu Z,et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy[J]. EMBO Rep,2014,15(5):566-75.
[42] Wu H,Xue D,Chen G,et al. The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy[J]. Autophagy,2014,10(10):1712-25.
[43] Chen M,Chen Z,Wang Y,et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy[J]. Autophagy,2016,12(4):689-702.
[44] Hirota Y,Yamashita S,Kurihara Y,et al. Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways[J]. Autophagy,2015,11(2):332-43.
R542.2
A
1674-4055(2017)10-1266-03
1430060 武漢,武漢大學(xué)人民醫(yī)院麻醉科
夏中元,E-mail:xiazhongyuan2005@aliyun.com
10.3969/j.issn.1674-4055.2017.10.36
本文編輯:阮燕萍