Mitochondria-targeted therapeutics, MitoQ and BGP-15, reverse aging-associated meiotic spindle defects in mouse and human oocytes.
Mitochondria-targeted therapeutics, MitoQ and BGP-15, reverse aging-associated meiotic spindle defects in mouse and human oocytes.
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DOI：
10.1093/humrep/deaa300
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发表时间：
2021-02-18
期刊：
影响因子：
--
通讯作者：
Carroll J
中科院分区：
文献类型：
--
作者：
Al-Zubaidi U;Adhikari D;Cinar O;Zhang QH;Yuen WS;Murphy MP;Rombauts L;Robker RL;Carroll J
线粒体靶向治疗能否逆转小鼠和人类卵母细胞中衰老和氧化应激诱导的纺锤体缺陷？在IVM期间暴露于MitoQ或bp -15可保护暴露于氧化应激或来自生殖年龄小鼠的小鼠卵母细胞免受纺锤体和染色体缺陷，而MitoQ可促进核成熟并保护人类卵母细胞免受染色体错位。随着母亲年龄的增长，卵母细胞的纺锤体和染色体异常更为普遍，增加了非整倍体、流产和唐氏综合症等遗传疾病的风险。卵母细胞功能受损的起源可能与线粒体功能障碍和活性氧（ROS）增加有关。在IVM期间，用MitoQ和/或bp -15处理年轻和年老小鼠的卵母细胞。为了直接诱导线粒体功能障碍，用H2O2处理卵母细胞，然后处理MitoQ和/或bp -15。未成熟的人卵母细胞在有或没有MitoQ的情况下培养。每个实验至少重复3次，数据采用非配对样本t检验或卡方检验进行分析。从1月龄、12月龄和18月龄小鼠的卵泡中获得未成熟的生发囊（GV）期卵母细胞。卵母细胞在IVM期间用MitoQ和/或bp -15处理。gv期人卵母细胞分别在有或没有MitoQ的情况下培养。活细胞成像检测线粒体膜电位和线粒体ROS。用免疫荧光标记法观察固定卵母细胞的减数分裂纺锤体和染色体排列，并用Imaris分析三维图像。在IVM中，MitoQ或bp -15对暴露于氧化应激的卵母细胞和老年小鼠卵母细胞的纺锤体和染色体缺陷具有保护作用（P < 0.001）。在人类卵母细胞中，MitoQ在IVM期间的存在促进了核成熟，并在防止染色体错配方面具有类似的积极作用（P < 0.001）。我们的研究确定了两种可能有助于提高老年妇女生育能力的优秀候选药物。然而，这些潜在的治疗方法必须在临床IVM系统中进行疗效测试，并在使用前在临床前模型中对所产生的后代进行彻底检查。我们使用体外系统对小鼠和人类卵母细胞成熟的结果提供了线粒体靶向分子（如MitoQ和bp -15）可能代表一种新的治疗方法，用于治疗与母体衰老相关的纺锤体和染色体异常的原理证明。该项目得到了澳大利亚国家卫生和医学研究理事会和澳大利亚研究理事会的财政支持。U.A.-Z。获伊拉克高等教育和科学研究部博士奖学金资助，O.C.获TUBITAK-1059B191601275资助。M.P.M.是MitoQ公司的顾问，并持有线粒体靶向治疗的专利。R.L.R.是使用BGP-15提高配子质量相关专利的发明人。N/A
Do mitochondria-targeted therapies reverse ageing- and oxidative stress-induced spindle defects in oocytes from mice and humans? Exposure to MitoQ or BGP-15 during IVM protected against spindle and chromosomal defects in mouse oocytes exposed to oxidative stress or derived from reproductively aged mice whilst MitoQ promoted nuclear maturation and protected against chromosomal misalignments in human oocytes. Spindle and chromosomal abnormalities in oocytes are more prevalent with maternal aging, increasing the risk of aneuploidy, miscarriage and genetic disorders such as Down’s syndrome. The origin of compromised oocyte function may be founded in mitochondrial dysfunction and increased reactive oxygen species (ROS). Oocytes from young and old mice were treated with MitoQ and/or BGP-15 during IVM. To directly induce mitochondrial dysfunction, oocytes were treated with H2O2, and then treated the MitoQ and/or BGP-15. Immature human oocytes were cultured with or without MitoQ. Each experiment was repeated at least three times, and data were analyzed by unpaired-sample t-test or chi-square test. Immature germinal vesicle (GV) stage oocytes from 1-, 12- and 18-month-old mice were obtained from preovulatory ovarian follicles. Oocytes were treated with MitoQ and/or BGP-15 during IVM. GV-stage human oocytes were cultured with or without MitoQ. Mitochondrial membrane potential and mitochondrial ROS were measured by live-cell imaging. Meiotic spindle and chromosome alignments were visualized by immunofluorescent labeling of fixed oocytes and the 3-dimensional images were analyzed by Imaris. MitoQ or BGP-15 during IVM protects against spindle and chromosomal defects in oocytes exposed to oxidative stress and in oocytes from aged mice (P < 0.001). In human oocytes, the presence of MitoQ during IVM promoted nuclear maturation and had a similar positive effect in protecting against chromosomal misalignments (P < 0.001). Our study identifies two excellent candidates that may help to improve fertility in older women. However, these potential therapies must be tested for efficacy in clinical IVM systems, and undergo thorough examination of resultant offspring in preclinical models before utilization. Our results using in-vitro systems for oocyte maturation in both mouse and human provide proof of principle that mitochondrially targeted molecules such as MitoQ and BGP-15 may represent a novel therapeutic approach against maternal aging-related spindle and chromosomal abnormalities. The project was financially supported by the National Health and Medical Research Council and Australian Research Council, Australia. U.A.-Z. was supported by the Iraqi Higher Education and Scientific Research Ministry PhD scholarship and O.C. was supported by TUBITAK-1059B191601275. M.P.M. consults for MitoQ Inc. and holds patents in mitochondria-targeted therapies. R.L.R. is an inventor on patents relating to the use of BGP-15 to improve gamete quality. N/A
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接受IVF-ISSI治疗的妇女中的辅酶Q10补充和卵母细胞倍倍性。
DOI：
10.4137/cmrh.s14681
发表时间：
2014
期刊：
Clinical medicine insights. Reproductive health
影响因子：
--
作者：
Bentov Y;Hannam T;Jurisicova A;Esfandiari N;Casper RF
通讯作者：
Casper RF
影响因子：
5.6
作者：
Dalton, Caroline M.;Szabadkai, Gyorgy;Carroll, John
通讯作者：
Carroll, John
影响因子：
9.2
作者：
Lister, Lisa Martine;Kouznetsova, Anna;Herbert, Mary
通讯作者：
Herbert, Mary
影响因子：
9.2
作者：
Chiang, Teresa;Duncan, Francesca E.;Schindler, Karen;Schultz, Richard M.;Lampson, Michael A.
通讯作者：
Lampson, Michael A.
影响因子：
2.2
作者：
Literati-Nagy, B.;Kulcsar, E.;Koranyi, L.
通讯作者：
Koranyi, L.