贺斌,郭会朵,赵茹茜*
(南京农业大学农业部动物生理生化重点实验室,江苏 南京 210095)
精子中线粒体的功能和命运
贺斌,郭会朵,赵茹茜*
(南京农业大学农业部动物生理生化重点实验室,江苏 南京 210095)
线粒体是细胞中最为重要的细胞器之一,通过氧化磷酸化产生ATP维持细胞正常生理功能,还参与钙离子稳态、细胞凋亡和类固醇激素合成等生物学过程。此外,线粒体是唯一含有功能性基因组(mtDNA)的细胞器。精子作为高度分化的生殖细胞,其线粒体与其他细胞存在许多异同之处。由于精子的特殊性,精子中线粒体的功能以及mtDNA是否遗传给子代方面的研究已成为关注的焦点。本文综述了精子线粒体和mtDNA的生物学特征、功能以及受精后的去向。
精子;线粒体;mtDNA;母系遗传
线粒体(mitochondria)是细胞中最为重要的细胞器之一,除了产生ATP之外,还参与了其它多种生理过程,如钙离子稳态、细胞凋亡、脂质和氨基酸代谢、类固醇激素合成等。线粒体不同于其它细胞器的一个重要特征是其含有自己的环状基因组,称之为线粒体 DNA(mitochondrial,mtDNA)。mtDNA 编码13个呼吸链蛋白,这对于线粒体功能非常重要。精子中线粒体与其他细胞中的线粒体存在许多相同之处,而作为生殖细胞中唯一携带遗传物质的细胞器,又具有很多独特的功能。相同之处在于精子线粒体同样参与能量供应,钙离子稳态等过程;不同之处在于,精子线粒体还参与了精子获能以及顶体反应等精子独有的功能。此外,精子作为父本遗传物质最重要的载体,其mtDNA是否参与遗传信息的传递尚不明确。本文对多种动物精子线粒体的生物学特征、功能和命运的研究进展进行综述。
1.1 线粒体形态
精子发生过程中,线粒体的形态处于动态的变化过程中。精原细胞和早期的精母细胞含有传统意义上的线粒体,晚期的精母细胞、精细胞和精子线粒体为高度浓缩状态,此时的线粒体代谢效率较强[1]。成熟精子中含有22-75个线粒体,线粒体相互连接,在鞭毛中段周围形成紧密的螺旋[2]。线粒体主要由线粒体外膜,线粒体内膜,膜间隙和线粒体基质构成,线粒体内膜折叠缠绕形成线粒体内嵴,线粒体内嵴具有呼吸链酶系及ATP酶复合体,参与呼吸链电子传递,在内膜可形成跨膜质子梯度,在ATP合成酶催化下将ADP生成ATP[3]。精子的运动依赖于线粒体提供能量。精子线粒体结构的改变会伴随其中各种能量代谢酶含量的改变,如细胞色素氧化酶、琥珀酸脱氢酶、乳酸脱氢酶同工酶含量的改变,会影响精子的供能,从而导致精子运动障碍[4]。由此可见,线粒体形态的完整性及其组分对于维持精子活力至关重要。
1.2 线粒体膜电位
线粒体在呼吸氧化过程中,将所产生的能量以电化学势能储存于线粒体内膜,在内膜两侧造成质子及其他离子浓度的不对称分布而形成线粒体膜电位(Mitochondrial membrane potential),正常的线粒体膜电位是维持线粒体进行氧化磷酸化和产生三磷酸腺苷的先决条件。线粒体膜电位是反映线粒体功能的主要指标,可以指示线粒体的能量状态,常被作为评估线粒体呼吸链和电子传递的活性[5]。大量研究表明,精子线粒体膜电位与精子活力及体外受精能力密切相关,高线粒体膜电位是精子活力的必备条件[6-9]。
1.3 线粒体DNA
线粒体是唯一含有功能性基因组的细胞器,线粒体基因组是双链环状的DNA,15-17 kbp,由37个基因构成,其中包括13个多肽、22个转运RNA(tRNA)和 2个核糖体 RNA(rRNA),所编码的 13个多肽是线粒体电子传递链的最主要成分。小鼠精子中含有约50-75个mtDNA拷贝数,而人类精子中含有约1500个mtDNA拷贝数[10-11]。mtDNA位点缺失或者突变都可以导致精子活力降低,有文献报道mtDNA 4977 bp位点缺失会造成精子活力下降和男性不育[12],而mtDNA 4696 bp位点缺失导致小鼠精子结构异常[13]。研究发现,不育男性精子中mtDNA拷贝数显著高于正常精子,而mtDNA完整性明显降低[14-15]。对此,有2种解释:一是不正常精子为了弥补线粒体呼吸链活性不足,所以增加了其mtDNA含量;另一种是在不育患者精子中,其mtDNA增加是精子发育异常的表现。mtDNA的转录和翻译受到核基因编码的转录因子的调节,在人精子中发现,此类转录因子的含量及其转位线粒体的过程与精子质量密切相关[16]。Jodar等提取精子RNA进行芯片分析发现,异常精子中mtDNA转录的RNA丰度显著低于正常精子[17]。总之,mtDNA与精子质量间存在相关性,但其确切关系尚未完全明确。
2.1 线粒体参与能量供应
精子的各种生理活动均需要大量的能量供应,而精子中ATP主要通过2种代谢方式产生:糖酵解和氧化磷酸化(Oxidative phosphorylation,OXPHOS),前者主要在精子头部和尾部发生,后者主要在精子中段线粒体分布区域发生[18]。然而,对于精子优先利用何种能量代谢方式,一直存在争议。有文献报道,OXPHOS是精子中主要的能量代谢方式,线粒体膜电位和氧气的消耗量与ATP含量和精子活力呈正相关[19-21]。在精子尾部的纤维鞘内存在多种糖酵解的关键酶[22],小鼠精子糖酵解酶缺失会导致不育[23-25]。此外,使用解偶联剂CCCP抑制线粒体OXPHOS发现小鼠精子活力并不受影响,且精子中ATP量基本不变。如果ATP仅仅是由线粒体呼吸产生,由于线粒体只位于精子中段,那么ATP就需要通过自由扩散到达精子尾部,这显然不能满足鞭毛高速运动所需的大量ATP,而糖酵解所需的酶类都位于精子的尾部,因此,糖酵解是小鼠精子鞭毛运动所需ATP的主要来源[26]。事实上,精子能量供应方式存在物种差异。有些物种,如猪、马的精子线粒体OXPHOS作用较强,仅依靠糖酵解并不能维持精子活力[8,27-28];而有些物种,如牛线粒体OXPHOS和糖酵解均较强[29];而小鼠、大鼠和人类,其精子ATP主要依赖于糖酵解供应[30]。
使用丙酮酸或乳酸代替培养基里的葡萄糖时,小鼠精子的活力和ATP量维持不变,但是如果此时加入CCCP以抑制线粒体呼吸,精子的活力和ATP量均大大降低[26]。由此可见,精子所处的微环境中能量代谢底物可影响精子的代谢方式。由于OXPHOS比糖酵解产生的ATP较多,线粒体主要集中在哺乳动物精子中段,可能可以利用更多物质(脂肪酸、单羧酸、氨基酸)产生能量,这时OXPHOS可能作为ATP主要的产生方式[31-32]。由此可见,糖酵解和OXPHOS共同参与能量供应的过程。在不同的环境中或不同的生理状态下,其能量供应方式也会不同。当糖酵解的底物很少时,精子会启动利用线粒体呼吸获得ATP。
2.2 线粒体参与钙离子(Ca2+)稳态
Ca2+在精子中起着重要作用,其调节精子很多功能,如精子运动、精子获能、超活化和顶体反应[33]。线粒体是胞内Ca2+的贮存场所,线粒体内的Ca2+浓度对于线粒体的ATP合成、线粒体通透性及细胞质内钙信号的调节具有重要影响[34-35]。体细胞线粒体可通过线粒体钙离子转运体摄取Ca2+,从而调控胞内Ca2+浓度、细胞代谢和存活能力,同时,精子中也存在线粒体钙离子转运体[36]。依赖线粒体活性的精子活力可被外源Ca2+明显抑制,而依赖糖酵解的精子活力并不受影响,在线粒体膜被除去或者干扰线粒体功能之后,额外添加ATP或钙离子,精子活力将得到明显提高[37]。线粒体通过富集和释放Ca2+以维持钙离子稳态,从而介导一些胞内反应,另外基质内Ca2+富集可促进能量的产生,进而增加胞内ATP含量,从而提高精子活力[38]。
2.3 线粒体参与精子凋亡
目前,研究已发现,多种凋亡信号均可作用于线粒体,促进膜间腔促凋亡因子的释放,启动线粒体介导的凋亡(apoptosis)通路。由于精子缺乏胞质成分,学者们对精子能否发生凋亡仍有疑问。事实上,精子可表现多种凋亡特征,如Caspases激活、磷脂酰丝氨酸外翻、DNA损伤等[39-40]。此外,线粒体Annexin V染色可指示精子质量,而Caspase激活与精子质量低下和受精能力弱存在相关性,这些现象均表明精子凋亡与精子活力存在密切联系。研究发现,Caspase主要集中在精子中段、线粒体分布的部位[41],而使用凋亡诱导剂可增加Caspase活性[42],从而证明精子线粒体可能参与凋亡过程。活性氧(Reactive oxygen species,ROS)可使精子DNA受到损伤,进而引起精子凋亡[43]。线粒体是ROS产生的主要场所,ROS作为OXPHOS的副产物,起着重要的作用。在精子中,线粒体复合物Ⅰ和Ⅲ是ROS产生的主要位点[44]。生理范围内的ROS参与多项精子功能调节,如活力、获能、顶体反应、超活化和受精等[45-47],而超出生理范围的ROS会导致精子存活、活力和线粒体膜电位下降,精子形态不完整,DNA损伤和脂质过氧化,最终导致其凋亡[44,48-49]。此外,线粒体内Ca2+浓度升高可引起细胞色素氧化酶系统功能失调,导致氧化单电子还原成氧自由基增多,诱发精子凋亡。
2.4 线粒体参与精子获能
精子获能(capacitation)是精子获得穿透卵子透明带能力的生理过程。随着精子的获能,氧耗量增加,精子运动加速,线粒体发生松散。牛和猪精子体外获能和孕酮诱导的顶体反应中均观察到耗氧峰值,因此,推测线粒体在此过程中发挥了重要作用[50-51]。此外,精子获能过程中伴随有蛋白质的磷酸化尤其是酪氨酸的磷酸化,有研究已证实精子中多种线粒体蛋白参与了精子获能所依赖的蛋白酪氨酸磷酸化过程[52]。
3.1 线粒体母系遗传
大量的细胞谱系与种族发育学的研究结果均显示,子代线粒体是由母本遗传而来,即母系遗传(Maternal inheritance)[53-54]。在受精过程中,精子所携带的mtDNA易受到活性氧的损伤,损伤的mtDNA遗传给子代将导致线粒体功能障碍和线粒体相关疾病[55]。因此,在进化过程中,机体保留了一系列精子线粒体和mtDNA的清除机制。目前报道的精子线粒体和mtDNA清除包括两阶段:在精子形成期,线粒体的数量逐渐减少;受精后,受精卵中mtDNA迅速被降解。
3.2 受精前线粒体清除
精子发生过程中,其胞质成分大部分丢失,只含有较少细胞器,其中最主要的细胞器是线粒体[56]。精子发生过程中伴随着mtDNA拷贝数减少,这一现象主要发生在圆形精细胞向长形精子转化的过程中,含有精细胞细胞质成分的残余体被支持细胞吞噬[57]。Diez-Sanchez[11]发现向前运动和不向前运动精子中mtDNA拷贝数分别是700和1200。Luo等[58]通过密度梯度离心方法分离了不同活力的小鼠精子,统计发现高活力精子和低活力精子中mtDNA拷贝数分别是1.29和45.93,即能进入输卵管发生受精的高活力精子几乎不含有mtDNA。类似结果在猪精子中得到了验证[8]。此外,为阐明不同活力精子中线粒体活性是否存在差异,Guo等[8]比较了不同活力猪精子线粒体的特征及其调节因素,结果表明,尽管高活力精子线粒体数量少于低活力精子,但线粒体生物合成能力显著高于低活力精子。在线虫精子发生过程中,mtDNA可被核酸内切酶G降解,使得受精前精子中仅留下无mtDNA的空泡状线粒体[59]。可见,精子线粒体清除是精子发生过程中的重要过程,而mtDNA拷贝数可能是精子质量的重要指标。然而,精子线粒体清除是否是精子的一种积极主动行为,线粒体清除后是否促进了精子活力的提高,还有待进一步研究。
3.3 受精后线粒体清除
也有观点[60]认为,精子发生过程中线粒体内核酸开始发生降解,到受精后源于精子的mtDNA被迅速降解而丢失,使得早期胚胎留下空泡状的精子线粒体。也有证据[61]表明精子线粒体在早期胚胎中以泛素化的方式发生降解。Sato等[62]以线虫为研究对象,将线虫精子中的线粒体进行染色标记后进行受精,观察受精卵中线粒体的动态变化,发现来自精子的线粒体在受精卵中以自噬的方式降解,该结论在自噬缺陷型线虫得到了进一步的验证,自噬缺陷的受精卵中精子线粒体和所携带的基因组能被遗传给幼虫。与此不同,Luo等[58]利用2种转基因小鼠品系,一种携带绿色荧光蛋白GFP标记的自噬体,另一种携带红色荧光蛋白标记的线粒体,证实自噬并未参与小鼠受精后精子线粒体的清除。最近,Zhou等[63]在秀丽隐杆线虫的研究中发现,受精后精子线粒体核酸内切酶CPS-6从线粒体膜间质转位到线粒体基质里面,对线粒体DNA进行降解、清除。除此之外,也有观点[58]认为精子线粒体在受精过程中进入到了受精卵,得以保存,只是在卵裂过程中,精子线粒体非平均地分配到卵裂球中,被大量的母本线粒体稀释,故而子代个体中只有部分细胞可检测到父本线粒体。综上所述,精子线粒体在受精后可能存在泛素化、自噬和核酸酶降解等多种降解方式,使得精子线粒体保存到子代的可能性非常小,但不能完全排除精子线粒体遗传给子代的可能性。
4.1 精子线粒体生物学特征研究展望
线粒体电子传递链是由核基因组和mtDNA编码的蛋白共同组成,核编码的蛋白在胞浆内表达后,在一系列伴侣分子的作用下,转位至线粒体,完成组装之后才能发挥功能[64-65]。虽然精子成熟后,其转录活性基本消失,但仍具有较强的转录后调节和翻译活性,且其翻译过程受到精密的调节[66]。此外,精子中还存在蛋白翻译后调节,如磷酸化、乙酰化、糖基化和泛素化等[67]。因此,深入研究和探明精子内线粒体相关的蛋白翻译、修饰和线粒体转位的过程将有助于理解线粒体的结构和功能。
4.2 精子线粒体功能研究展望
目前,对精子线粒体的功能已有大量报道,尽管现在已明确线粒体对精子质量至关重要,但其具体发挥的作用尚未完全明确。目前已知线粒体主要参与精子的能量供应、钙稳态和获能等过程,精子线粒体是否与其他细胞中的线粒体一样,参与细胞凋亡、类固醇激素合成等过程尚不明确。此外,已有报道对精子线粒体功能的研究主要是以啮齿类动物为模型,然而不同物种间线粒体功能存在较大差异,因此,深入研究和阐明各个物种精子线粒体的功能,将有助于提高饲养动物的繁殖力。
4.3 精子线粒体命运研究展望
精子线粒体命运是目前生命科学研究的热点领域,精子线粒体及mtDNA清除的机制呈现多样化。然而,精子线粒体和mtDNA的清除到底发生在何时,何处?受到哪些信号的调节?线粒体清除后精子是否拥有更强的受精能力?这些均有待进一步研究。对上述问题的研究,不仅有助于理解线粒体母系遗传机制,还有助于诊断和治疗线粒体相关的男性不育和遗传性疾病。
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Role and fate of mitochondria in sperm
He Bin,Guo Huiduo,Zhao Ruqian*
(KeyLaboratory of Animal Physiology and Biochemistry,Ministry of Agriculture,Nanjing Agricultural University,Nanjing,Jiangsu 210095,China)
Mitochondria play important role in oxidative phosphorylation,calcium homeostasis,apoptosis,and steroidogenesis.Moreover,mitochondria is the only organelle that contains its own functional genome.Sperm is a highly differentiated gamete.Although the mitochondria in the sperm share many common features with those in other somatic cells,they show some unique characteristics.To date,the role of mitochondria in sperm and its final fate are still controversial.Here,we review the current understanding of the mitochondria and their mtDNA,including the biological characteristics,the functions,and the fate after fertilization.
sperm;mitochondria;mitochondrial DNA(mtDNA);maternal inheritance
S811.2
A
10.13880/j.cnki.65-1174/n.2017.02.001
1007-7383(2017)02-0133-06
2017-03-10
国家重点研发计划项目(2016YFD0500502),国家自然科学基金项目(31502027)
贺斌(1984-),男,讲师,从事动物生殖生理学研究。
*通信作者:赵茹茜(1964-),女,教授,从事动物生理学与动物福利研究,e-mail:zhao.ruqian@gmail.com。