线粒体功能障碍与卵巢早衰的研究进展

doi:10.3877/cma.j.issn.2095-655X.2023.04.013

卵巢早衰(POF)是一种常见的生殖内分泌疾病，主要表现为因卵巢功能衰竭所致的提前闭经，严重影响女性健康。线粒体作为重要细胞器，不仅具有供能作用，还参与细胞分化、信息传递和凋亡等各种生命活动，其功能障碍与POF发生有关。笔者主要从线粒体能量代谢失衡、线粒体钙代谢失衡、线粒体DNA突变及线粒体动力学改变4个方面综述线粒体异常对POF的影响，并通过总结该疾病的相关机制，对POF的治疗方案作出相应见解及未来展望。

关键词: 卵巢早衰, 线粒体DNA, 线粒体能量代谢, 钙代谢, 线粒体动力学

Premature ovarian failure (POF) is a common reproductive endocrine disorder that mostly appears as premature amenorrhea due to ovarian failure and has a significant negative impact on the health of women. As significant organelles, mitochondria play multiple roles in a variety of biological processes, including cell development, information transmission, and apoptosis, whose malfunction is thought to result in the occurrence of POF. The authors mainly investigate the consequences of mitochondrial abnormalities on POF from 4 viewpoints, namely, imbalanced mitochondrial energy metabolism, imbalanced mitochondrial calcium metabolism, mitochondrial DNA mutation, and mitochondrial dynamics changes. By outlining the disease′s pertinent mechanism, the treatment plan for POF is evaluated together with its future prospects.

Key words: Premature ovarian failure, Mitochondrial DNA, Mitochondrial energy metabolism, Calcium metabolism, Mitochondrial dynamics

图1 线粒体能量代谢失衡导致卵巢早衰机制示意图注：Lonp1活性降低或缺失，导致线粒体复合物Ⅰ、Ⅲ、Ⅳ和Ⅴ形成减少，致使ATP生成障碍，导致POF的发生；Lonp1活性降低或缺失也能直接抑制卵母细胞发育，进而卵母细胞死亡、卵巢储备丧失，最终导致POF发生；Lonp1为线粒体Lon蛋白酶P1；ATP为腺嘌呤核苷三磷酸；POF为卵巢早衰；由WPS作图

图2 线粒体钙代谢失衡导致卵巢早衰机制示意图注：ROS促进ER中的Ca²⁺释放，导致线粒体钙超载，mPTP开放，Ca²⁺、ROS和NAD⁺进入线粒体，导致ATP生成障碍，导致Δφm下降，卵母细胞和颗粒细胞死亡，继而发生POF；ROS为活性氧；ER为内质网；mPTP为线粒体通透性转换孔；NAD⁺为烟酰胺腺嘌呤二核苷酸；Δφm为线粒体膜电位；ATP为腺嘌呤核苷三磷酸；POF为卵巢早衰；由WPS作图

图3 线粒体DNA突变导致卵巢早衰机制示意图注：线粒体tRNA^Leu(UUR)C3303T、tRNA^MetA4435G、tRNA^GlnT4363C、tRNA^CysG5821A和tRNA^ThrA15951G突变，促进ROS生成，抑制ATP生成，导致线粒体功能障碍，发生POF。线粒体特异性聚合酶γ的POLGA亚基突变或缺失，导致mtDNA复制异常，导致POF发生；ROS为活性氧；ATP为腺嘌呤核苷三磷酸；POLGA为DNA聚合酶γ的催化亚基；mtDNA为线粒体DNA；POF为卵巢早衰；由WPS作图

图4 线粒体动力学异常导致卵巢早衰机制示意图注：线粒体动力学主要从3个方面导致POF发生，包括敲除线粒体融合相关基因Mfn2，导致类固醇生成障碍；mtDNA突变，抑制线粒体融合和线粒体分裂发生；Beclin 1基因缺失，导致线粒体自噬异常；POF为卵巢早衰；Mfn2为线粒体融合蛋白2；mtDNA为线粒体DNA；Beclin1为酵母Atg6自噬基因的哺乳动物直系同源物；由WPS作图

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Research progress of mitochondrial dysfunction and premature ovarian failure

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