線粒體鈣蛋白酶系統(tǒng)

常泓，尹淑琴，袁建琴

(1.山西農(nóng)業(yè)大學(xué)期刊社，山西 太谷 030801； 2.山西農(nóng)業(yè)大學(xué) 生命科學(xué)學(xué)院，山西 太谷 030801)

線粒體鈣蛋白酶系統(tǒng)

常泓1，尹淑琴2，袁建琴2

(1.山西農(nóng)業(yè)大學(xué)期刊社，山西 太谷 030801； 2.山西農(nóng)業(yè)大學(xué) 生命科學(xué)學(xué)院，山西 太谷 030801)

[目的]綜述線粒體蛋白酶系統(tǒng)的成員、功能及調(diào)控。[方法]文獻(xiàn)綜述法。[結(jié)果]鈣蛋白酶一直被看作是細(xì)胞質(zhì)酶，但是近幾年的研究證明CAPN1、CAPN2和CAPN10存在于線粒體中，并在壞死和凋亡細(xì)胞死亡等一系列病理生理情況下起重要作用。[結(jié)論]本文概述了線粒體蛋白酶系統(tǒng)的主要特征及它在細(xì)胞、普通生化和病理生理學(xué)中的一些作用。

線粒體； CAPN1； CAPN2； CAPN10； 鈣蛋白酶抑制蛋白； 細(xì)胞凋亡

鈣蛋白酶是鈣激活半胱氨酸蛋白酶的一個成員，它廣泛分布于細(xì)胞和亞細(xì)胞器中，同時存在的還有它們的內(nèi)源性抑制劑：鈣蛋白酶抑制蛋白和它們的激活因子UK114和ACBP。鈣蛋白酶家族是由普遍存在的鈣蛋白酶如：CAPN1(也稱μ鈣蛋白酶)，CAPN2(也稱m鈣蛋白酶)，CAPN10和組織特異性鈣蛋白酶CAPN3(也稱為p94)即特異性肌蛋白，CAPN8(胃nCl-2)，CAPN9(消化細(xì)管nCl-4)等15種鈣蛋白酶組成的[1]。最近的研究已經(jīng)證明了CAPN1、CAPN2、CAPN10和它們的內(nèi)源性抑制劑鈣蛋白酶抑制蛋白存在于線粒體中[2,3]。

線粒體參與許多不同的過程，如凋亡、新陳代謝、疾病、老化、貯存和Ca2+的釋放等[2]。在不同的病理生理環(huán)境下，[Ca2+]m濃度的增加會引發(fā)一系列破壞性的循環(huán)，對細(xì)胞的破壞是不可逆的。[Ca2+]i濃度的增加會造成鈣蛋白酶活性的增加，隨后細(xì)胞內(nèi)的一些蛋白質(zhì)會被限制性蛋白酶降解，這種影響會比其他可逆的鈣依賴過程如磷酸化和去磷酸化產(chǎn)生更大的破壞[4]。在缺血時，細(xì)胞內(nèi)Ca2+的動態(tài)平衡改變，但是線粒體能夠在一定程度上使細(xì)胞質(zhì)中Ca2+的濃度得到緩沖，這就表明線粒體具有運(yùn)輸Ca2+的能力[5,6]。

在線粒體中，Ca2+主要由釕紅敏感性轉(zhuǎn)運(yùn)體通過質(zhì)子電化學(xué)梯度驅(qū)動，并主要由鈉鈣交換體介導(dǎo)Ca2+流動，從而導(dǎo)致連續(xù)的Ca2+再循環(huán)穿過線粒體膜，造成細(xì)胞質(zhì)和線粒體中Ca2+水平的不斷改變[7]。鈉鈣交換體介導(dǎo)的線粒體釋放Ca2+是在生理學(xué)和病理生理學(xué)環(huán)境下[Ca2+]i濃度做出回應(yīng)的一種形式[7]，Drumond[8]等人證明了[Ca2+]i的增加會造成[Ca2+]m的增加。在非正常生理環(huán)境下，[Ca2+]i濃度的升高導(dǎo)致線粒體失調(diào)，進(jìn)而導(dǎo)致細(xì)胞機(jī)能失調(diào)[8,9]。在細(xì)胞凋亡中，廣泛表達(dá)的CAPN1和CAPN2不斷活化，使[Ca2+]i濃度增加。特別是，CAPN1導(dǎo)致的線粒體膜內(nèi)鈉鈣離子交換體的蛋白水解作用，在使Ca2+增加，通過凋亡誘導(dǎo)因子(AIF)的釋放導(dǎo)致細(xì)胞的死亡中起到非常重要的作用[10,11]。因此，線粒體鈣蛋白酶介導(dǎo)細(xì)胞死亡和一些病理生理學(xué)環(huán)境下的許多疾病有密切的聯(lián)系。

1 線粒體中的鈣蛋白酶

雖然鈣蛋白酶已經(jīng)被看作是細(xì)胞質(zhì)酶，但是在最近的研究中表明鈣蛋白酶也存在于線粒體中，且參與線粒體中天冬氨酸轉(zhuǎn)氨酶(AAT)和凋亡誘導(dǎo)因子的切割[12,13]。線粒體中CAPN1的生化特征和細(xì)胞質(zhì)中CAPN1相似[2,3]，線粒體CAPN1包含有一個80 kDa的起催化作用的大亞基以及一種28 kDa起調(diào)節(jié)作用的小亞基[3,14]。大量研究表明，CAPN10存在于線粒體中，并且參與調(diào)節(jié)鈣誘導(dǎo)的線粒體機(jī)能失調(diào)，是通過電子傳遞鏈將復(fù)合亞基分開來調(diào)節(jié)的[15]。Badugu[16]等人已經(jīng)證明了目前位于線粒體膜間隙的CAPN1包括大亞基和小亞基，大亞基的N端存在一種線粒體靶位序列，同時小亞基在線粒體中依附在大亞基上。Arrington[17]等人也證明了CAPN10也有靶位序列，線粒體CAPN10不包含結(jié)構(gòu)域IV，說明CAPN10和CAPN1、CAPN2存在本質(zhì)上的不同。Ozaki[3]等人最近也報道了CAPN2目前也存在于線粒體膜間隙，它包含有80 kDa的起催化作用的大亞基，同時也存在30 kDa起調(diào)節(jié)作用的小亞基。Beer[18]等人的研究表明有兩種活化的鈣蛋白酶存在于鼠肝線粒體中，一種是由25 μmol·L-1Ca2+激活的活性為最大活性一半的鈣蛋白酶，另一種則由750 μmol·L-1Ca2+激活的。此外，Tavares[19]等人發(fā)現(xiàn)，膜間隙存在兩種有活性的鈣蛋白酶，還有3種存在于鼠肝線粒體基質(zhì)中。

2 線粒體鈣蛋白酶的調(diào)控

最近，Kar[20]等人報道了肺動脈平滑肌線粒體中含有145 kDa的鈣蛋白酶抑制劑(clpastatin)，有XL結(jié)構(gòu)域；還含有120 kDa和110 kDa鈣蛋白酶抑制劑分子，沒有XL結(jié)構(gòu)域，但有L結(jié)構(gòu)域。Kar[2]等人證明了，在生理環(huán)境下Ca2+條件下，CAPN1-鈣蛋白酶抑制劑復(fù)合體存在于線粒體中，表明線粒體CAPN1被鈣蛋白酶抑制劑嚴(yán)格調(diào)控。

Ozaki[13]等人證明了線粒體CAPN1被ERP57調(diào)節(jié)，ERp57(亦稱為ER60，ERp60，ERp61，GRp58)是蛋白二硫鍵異構(gòu)酶(PDI)的一種家族成員。最初被發(fā)現(xiàn)存在于鼠肝的內(nèi)質(zhì)網(wǎng)中[21]，ERp57也被發(fā)現(xiàn)存在于細(xì)胞質(zhì)[22]和細(xì)胞核中[23]，并且參與糖蛋白的正確折疊以及對錯誤折疊的二硫鍵進(jìn)行重排[24,25]。最近的研究發(fā)現(xiàn)，ERp57還具有內(nèi)質(zhì)網(wǎng)分子伴侶的功能[26～28]。ERp57在MHC I類2肽轉(zhuǎn)運(yùn)中起重要作用，通過結(jié)合一種轉(zhuǎn)運(yùn)體參與抗原處理TAP復(fù)合體[29,30]。Ozaki[13]等人還證明了ERp57主要存在于線粒體OM中，且與目前存在于細(xì)胞質(zhì)中的ERp57不同，他們也證明了線粒體CAPN1與ERp57結(jié)合，但是細(xì)胞質(zhì)中的CAPN1和CAPN2不能與ERp57結(jié)合。這些研究者還證明了ERp57在再折疊線粒體CAPN1大亞基中發(fā)揮重要功能，即參與二硫鍵結(jié)構(gòu)和功能的形成。Herrmann[31]等人的研究表明線粒體膜間隙蛋白(IMS)需折疊形成二硫鍵，因?yàn)榈鞍踪|(zhì)在ISM中會氧化?？傊?，線粒體CAPN1可與ERp57結(jié)合，為理解線粒體中CAPN1的定位和調(diào)節(jié)機(jī)制提供了重要的線索[13]。

最近的研究也表明了線粒體中也包含了CAPN2，它和ERp57有關(guān)，且對切割從線粒體中釋放的AIF起重要作用[3]。ERp57是一種重要的分子伴侶，屬于熱激蛋白70家族[32～34]。它具有多種功能，包括進(jìn)入線粒體；適當(dāng)折疊新合成的細(xì)胞核和線粒體編碼的蛋白質(zhì)；在一些遭受壓力的情況下做出反應(yīng)，如葡萄糖匱乏、喪失氧化性及紫外線放射等[35]。ERp75在折疊線粒體CAPN2大亞基中起重要作用，這種折疊可能參與二硫鍵的形成以形成功能性的構(gòu)象[3]。

線粒體中除了CAPN1和CAPN2外，還有CAPN10[17]，CAPN10是一種非典型的鈣蛋白酶，且最近由于與II型糖尿病有密切關(guān)系而倍受關(guān)注。Giguere[36]等人確定鈣蛋白酶存在于兔中，小鼠、大鼠腎線粒體有大量75 kDa(CAPN10a)，56 kDa(CAPN10c或10 d)和50 kDa(CAPN10e)剪接變異體分子。CAPN10的可變剪接已被證明可產(chǎn)生8種不同大小的基因產(chǎn)品[36]。Arrington[17]等人還證明了兔子線粒體CAPN10是Ca2+誘導(dǎo)復(fù)合體I蛋白質(zhì)分裂的原因。雖然一些研究已經(jīng)證明CAPN10存在于線粒體基質(zhì)中，但是CAPN10的作用機(jī)制目前尚不清楚[17,36]。

3 線粒體鈣蛋白酶的功能

[Ca2+]i的增加導(dǎo)致線粒體中Ca2+超載，使線粒體鈣蛋白酶激活，最終導(dǎo)致細(xì)胞凋亡[11]。Kar[10]等人認(rèn)為線粒體中Ca2+的主要排出方式為鈉鈣離子交換體，在[Ca2+]m增加時被線粒體CAPN1切割，且在平滑肌細(xì)胞凋亡中起重要作用[10,11]。實(shí)驗(yàn)表明，主要的凋亡信號是從線粒體跨膜間隙釋放凋亡蛋白，如細(xì)胞色素C、AIF、Smac/DIABLD和Omi/HtrA2。在釋放這些蛋白質(zhì)時，可以通過活化依賴性和非依賴性半胱氨酸蛋白酶路徑促進(jìn)細(xì)胞凋亡。細(xì)胞色素C和Apaf1、dATP和酶原9一起形成凋亡復(fù)合體，在細(xì)胞質(zhì)中引發(fā)酶原9的自催化活化和啟動下游半胱氨酸蛋白酶級聯(lián)反應(yīng)。與細(xì)胞色素C相比，AIF是一種非依賴性半胱氨酸蛋白酶死亡因子，在釋放時可能遷移到細(xì)胞核中，且參與細(xì)胞質(zhì)凝集和大規(guī)模的DNA分解[37～39]。

線粒體鈣蛋白酶通過非依賴性半胱氨酸蛋白酶程序性細(xì)胞凋亡路徑在細(xì)胞凋亡中發(fā)揮重要作用，另外可促進(jìn)通透性轉(zhuǎn)換孔的形成，鈣蛋白酶在AIF的釋放中起直接的作用。鈣蛋白酶現(xiàn)已被證明參與AIF的切割并誘導(dǎo)其從線粒體中釋放[15,40,41]。線粒體中AIF的釋放與凋亡蛋白酶12的活化有關(guān)，凋亡蛋白酶12是另一個鈣蛋白酶底物[42]，因此即使鈣蛋白酶出現(xiàn)下調(diào)形成凋亡蛋白酶調(diào)節(jié)細(xì)胞死亡，由于AIF誘導(dǎo)機(jī)制，它也可能同時促進(jìn)凋亡蛋白酶非依賴程序性細(xì)胞死亡。

AIF核轉(zhuǎn)位作為凋亡蛋白酶非依賴性細(xì)胞死亡這一通路最近已在神經(jīng)元損傷中建立，包括視網(wǎng)膜感光細(xì)胞凋亡[41,43]和腦組織缺氧或缺血[15,44]。近期，Okiza[13]等人還證明了線粒體CAPN1切割成熟的AIF(62 kDa)并將tAIF(57 kDa)從線粒體IM釋放到IMS[13]。這就表明線粒體CAPN1是AIF誘導(dǎo)細(xì)胞死亡信號通路的一種引發(fā)劑。最近，Joshi[45]證明了線粒體CAPN1不參與AIF使用SH-SY5 Y神經(jīng)瘤細(xì)胞的程序，因此，線粒體CAPN1在特異性組織或特異性病理下切割A(yù)IF。

Ozaki[3]等人做了一項(xiàng)研究表明線粒體CAPN2在tAIF通過VDAC的蛋白酶加工而釋放進(jìn)入細(xì)胞質(zhì)中起非常重要的作用，AIF的釋放也發(fā)生在一些步驟中。首先，線粒體CAPN1切割與IM整合的AIF，且釋放進(jìn)IMS；第二，通過線粒體CAPN2的活化，通過切割VDAC和線粒體中凋亡蛋白的積累，IMS中可溶性的tAIF被釋放到細(xì)胞質(zhì)中。這樣，AIF從線粒體中釋放可能不僅被線粒體CAPN1限制，而且也被線粒體CAPN2限制[3]。這些觀察結(jié)果表明線粒體鈣蛋白酶的抑制作用可能對一些失調(diào)癥狀如色素性視網(wǎng)膜炎、視網(wǎng)膜變性或腦出血有一種潛在的治療作用[3]。

線粒體鈣蛋白酶在凋亡蛋白酶依賴和非依賴途徑的細(xì)胞凋亡中起重要作用。

3.1 依賴凋亡蛋白酶的細(xì)胞程序性死亡

鈣蛋白酶可能在細(xì)胞凋亡中發(fā)揮重要作用，通過凋亡蛋白酶家族成員的蛋白酶直接或間接地相互作用?，F(xiàn)已證明凋亡蛋白酶激活因子1將細(xì)胞色素C與活化的凋亡蛋白酶相結(jié)合，可被鈣蛋白酶切斷[46]。失去凋亡蛋白酶激活因子-1的原因是正確地誘導(dǎo)類凋亡蛋白酶3的活性，凋亡蛋白酶9中的鈣蛋白酶也導(dǎo)致了凋亡蛋白酶3活化能力的丟失。相反地，鈣蛋白酶裂解血小板7轉(zhuǎn)換為活化形式，不依賴于凋亡蛋白的活化。鈣蛋白酶和凋亡蛋白酶系統(tǒng)總是通過鈣蛋白酶抑制劑進(jìn)行調(diào)節(jié)[46]。凋亡蛋白酶已經(jīng)被證明能夠切割鈣蛋白酶抑制劑且降低它的抑制活性，由此在鈣蛋白酶和該蛋白酶抑制劑系統(tǒng)之間建立起一種復(fù)雜的互動，雖然鈣蛋白酶抑制劑的過度表達(dá)起初能夠增加凋亡蛋白酶3的活性，可能通過阻止鈣蛋白酶介導(dǎo)的凋亡蛋白酶9和凋亡蛋白酶3的降解，鈣蛋白酶抑制劑自身被凋亡蛋白酶3降解，導(dǎo)致鈣蛋白酶活性第二次增加[46]。

3.2 凋亡蛋白酶非依賴的程序性死亡

除了促進(jìn)線粒體通透性轉(zhuǎn)換孔的形成，鈣蛋白酶可能在AIF的釋放中也起直接的作用[5,40]。最近已有研究證明鈣蛋白酶能切割A(yù)IF，且能誘導(dǎo)其從線粒體中釋放。從線粒體中釋放的AIF最近已被觀察到與另一種鈣蛋白酶底物凋亡蛋白酶12的活性有關(guān)[42]。因此，盡管鈣蛋白酶出現(xiàn)了凋亡蛋白酶誘導(dǎo)細(xì)胞死亡形式的下調(diào)，但是它可能也同時通過AIF誘導(dǎo)機(jī)制促進(jìn)凋亡蛋白酶非依賴的程序性死亡[42]。鈣蛋白酶的Ca2+活化對生理學(xué)功能非常重要，但是過多的Ca2+會產(chǎn)生導(dǎo)致蛋白水解酶異?；钚?、細(xì)胞損傷甚至死亡[47]。MPT是由于Ca2+超載導(dǎo)致線粒體機(jī)能失調(diào)的一種形式，腺嘌呤核苷酸濃度降低，線粒體膜電位下降，氧化應(yīng)激性增加，以張開毛孔和線粒體腫脹為特征[48～50]。CAPN10的過度表達(dá)已經(jīng)被證明可以誘導(dǎo)線粒體分裂和增大，這與MPT一致，且這種線粒體形態(tài)學(xué)的改變被MPT抑制劑阻止[51]。另外，高水平CAPN10的表達(dá)可誘導(dǎo)線粒體自我吞噬，這一過程被3-甲基腺嘌呤阻止，且被MPT誘導(dǎo)刺激[50,52,53]。Arrington[17]等人證明30%的MPT被鈣蛋白酶抑制劑抑制，和Gores[54,55]等人觀點(diǎn)一致。Gores等人證明了肝臟線粒體類鈣蛋白酶激活調(diào)節(jié)MPT，他們也證明了CAPN10不能直接調(diào)節(jié)MPT，且線粒體分裂可能被除CAPN10之外的其他鈣蛋白酶調(diào)節(jié)。因此，當(dāng)CAPN10的生理學(xué)和病理生理學(xué)沒有被廣泛研究，它在蘭尼堿誘導(dǎo)細(xì)胞凋亡，GLUT4囊泡轉(zhuǎn)運(yùn)，胰腺的β細(xì)胞外排，白內(nèi)障，高甘油三酯血癥和II型糖尿病中起作用[17,56～59]。線粒體越來越被認(rèn)為是細(xì)胞死亡的檢測點(diǎn)，是細(xì)胞壞死和凋亡被送去下游加工的信號。CAPN10在這些疾病中發(fā)揮重要的作用，可通過它進(jìn)行疾病干預(yù)，處理細(xì)胞內(nèi)Ca2+動態(tài)平衡失調(diào)所誘導(dǎo)的疾病[17]。

4 線粒體鈣蛋白酶與神經(jīng)元細(xì)胞死亡

在過去的十年中，越來越多的證據(jù)表明凋亡蛋白酶非依賴性在神經(jīng)元細(xì)胞死亡中起到了極其重要的作用，AIF發(fā)揮主導(dǎo)中介作用[60.61]。關(guān)于AIF從線粒體中釋放有兩種機(jī)制，一是涉及到一種DNA修復(fù)酶聚合物活化的副產(chǎn)品PARP-1(poly(ADP-ribose)polymerase-1)，PARP-1的活化是AIF釋放的基礎(chǔ)[62,63]，且結(jié)果是產(chǎn)生高水平的毒害神經(jīng)的PAR(poly(ADP-ribose))聚合物[64]。此外，PAR聚合物和AIF遷移的誘導(dǎo)相關(guān)聯(lián)，這樣就提供了一種死亡信號機(jī)制，即將細(xì)胞核和神經(jīng)元線粒體連接起來[65]。第二種假設(shè)是控制AIF釋放和運(yùn)輸必需鈣蛋白酶的激活[15]，鈣失調(diào)廣泛存在于神經(jīng)元損傷和生理學(xué)的神經(jīng)元退行性疾病中[66]?；谶@些事實(shí)，最近已經(jīng)證明了鈣蛋白酶在切割A(yù)IF，和從獨(dú)立性腦和肝線粒體中釋放AIF起重要作用[40]。鈣蛋白酶活化和AIF N端分裂已被證明是AIF轉(zhuǎn)運(yùn)和缺血所致的神經(jīng)元死亡的原因[15]。最近，Vosler[67]等人證明了PARP-1誘導(dǎo)AIF釋放與鈣蛋白酶依賴AIF釋放緊密相連，PARP-1和鈣蛋白酶一致，在鈣失調(diào)時誘導(dǎo)缺血時AIF釋放[62,63,68～70]。除去現(xiàn)有概念外，重要的是依次激活PARP-1和鈣蛋白酶，PARP-1通過PAR聚合物誘導(dǎo)線粒體Ca2+失調(diào)而激活鈣蛋白酶。通過PAR聚合物誘導(dǎo)線粒體中Ca2+水平改變的機(jī)制目前還不清楚。一種機(jī)制認(rèn)為：PAR聚合物誘導(dǎo)線粒體透氣孔的形成導(dǎo)致Ca2+超載，有一項(xiàng)研究支持這一機(jī)制，即線粒體透氣孔抑制劑環(huán)孢霉素A介導(dǎo)的鈣誘導(dǎo)AIF從線粒體中釋放[40]。這種假設(shè)即PARP-1誘導(dǎo)線粒體Ca2+失調(diào)的有效性而誘導(dǎo)鈣蛋白酶活化是依賴于線粒體鈣蛋白酶。事實(shí)上，CAPN1擁有一段線粒體定位序列，且已經(jīng)在線粒體膜間隙發(fā)現(xiàn)[15,16,71]。Cao[15]等人證明了鈣蛋白酶是目前在線粒體膜內(nèi)或膜外伴隨著缺血性損傷，尤其是AIF是正常地存在于線粒體膜內(nèi)，因此，缺血損傷導(dǎo)致鈣蛋白酶和AIF共存。

當(dāng)[Ca2+]i增加到400 μmol·L-1時，線粒體Ca2+開始積累[72]，緩沖能力增大，線粒體基質(zhì)變得幾乎飽和，自由的線粒體Ca2+也將增加，自由的線粒體Ca2+的持續(xù)增加導(dǎo)致通透性轉(zhuǎn)換孔的開放和AIF的釋放。有NMDA毒性誘導(dǎo)的神經(jīng)元壓力使線粒體Ca2+增加,造成線粒體誘導(dǎo)POS產(chǎn)生和PARP活化[73]。在認(rèn)同這項(xiàng)研究的基礎(chǔ)上，Vosler[67]等人提出了兩種模型如圖5所示。首先，NMDA受體過度激活導(dǎo)致大量Ca2+內(nèi)流，線粒體作為一個水槽吸收過剩的Ca2+，然而，隨著[Ca2+]m的增加，氧氣增加，線粒體產(chǎn)能減少，這導(dǎo)致了超氧化物自由基釋放到胞質(zhì)中，細(xì)胞內(nèi)超氧化物可以與NO反應(yīng)，隨著引起NMDA受體的活化而形成過氧化亞硝酸鹽[72～77]，一種已知的分子可能對DNA產(chǎn)生嚴(yán)重的損傷[78]。

DNA損傷活化PARP-1產(chǎn)生PAR聚合物導(dǎo)致NAD嚴(yán)重減少，PAR聚合物水平超過了PAR聚合物分解酶的分解能力，已經(jīng)證明PARG能造成第二線粒體Ca2+凋亡[59,79]，或者，NAD耗盡可能引起嚴(yán)重的能量危機(jī)造成線粒體Ca2+失調(diào)[80,81]。Ca2+動態(tài)平衡導(dǎo)致線粒體鈣蛋白酶活化，切割線粒體內(nèi)的AIF，切割后從線粒體中釋放運(yùn)輸?shù)郊?xì)胞核內(nèi)，最后的階段是AIF誘導(dǎo)DNA加工和神經(jīng)最終死亡。因此，PARP-1活化伴隨著NMDA的暴露誘導(dǎo)線粒體Ca2+失調(diào)，隨后鈣蛋白酶活化且從線粒體中釋放。

5 結(jié)語與展望

本綜述著重于線粒體鈣激活酶系統(tǒng)，一個新興的鈣蛋白酶的研究領(lǐng)域，最近的研究表明，線粒體內(nèi)含有CAPN1，CAPN2和CAPN10。迄今為止，在已知的15種鈣蛋白酶中，這些線粒體鈣蛋白酶被鈣蛋白酶抑制劑-ERp復(fù)合蛋白、ERp57、ERp75調(diào)節(jié)[2,3,13]。最近，Kar[2]等人報道了線粒體鈣蛋白酶CAPN1被它的內(nèi)源性抑制劑鈣蛋白酶抑制劑所調(diào)節(jié)。Ozaki[3,13]等人證明了CAPN1和CAPN2目前存在于線粒體中代替鈣蛋白酶抑制劑，他們觀察到ERp57、ERp75分別和CAPN1、CAPN2相連?？梢灶A(yù)測，未來的研究一定會有CAPN1-鈣蛋白酶抑制劑相關(guān)晶體的研究，CAPN1-ERp57和CAPN2-ERp75晶體的研究可能對理解通過鈣蛋白酶抑制劑和ERp57、ERp75在線粒體中活化時對CAPN1或CAPN2的調(diào)節(jié)更起作用。

最近的研究證明了平滑肌和鼠肝線粒體沒有CAPN10[2,3]，有趣的是，Arringto[17]等人證明了腎線粒體僅包含鈣蛋白酶10，而不包含CAPN1和CAPN2，因此，可以研究在特異性組織和特異性生理學(xué)線粒體鈣蛋白酶體系的功能。

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(編輯：馬榮博)

Mitochondrial calpain system

Chang Hong1， Yin Shuqin2， Yuan Jianqin2

(1．PeriodicalPressofShanxiAgriculturalUniversity，Taigu030801，China； 2．CollegeofLifeScience，ShanxiAgriculturalUniversity,Taigu030801,China)

[Objective]The aim of this article was to overview the members, functions and regulations of calpains in mitochondrial. [Method] Literature review method. [Results]Calpain have previously been considered as the cytoplasmic enzymes, research in the recent past demonstrated that CAPN1, CAPN2 and CAPN10 are present in mitochondria, which play important roles in a variety of pathophysiological conditions including necrotic and apoptotic cell death phenomena. [Conclusion]This review outlined the key features of the mitochondrial calpain system, and its roles in several cellular and biochemical events under normal and some pathophysiological conditions.

Mitochondria， CAPN1， CAPN2， CAPN10， Calpastatin， Apoptosis

2017-01-06

2017-06-10

常泓(1968-)，女(漢)，山西榆次人，博士后，教授，研究方向：食品生物化學(xué)與分子生物學(xué)

國家自然科學(xué)基金(30271003)；山西省科技攻關(guān)項(xiàng)目(20090311037)；山西省青年基金項(xiàng)目(20021038)

Q55

A

1671-8151(2017)07-0469-08

特約稿件