Deepak Adhikari Ozgur Cinar Qing-Hua Zhang Wai Shan Yuen Michael P. Murphy Luk Rombauts Rebecca L. Robker John Carroll
Abstract
STUDY QUESTION
Do mitochondria-targeted therapies reverse ageing- and oxidative stress-induced spindle defects in oocytes from mice and humans?
SUMMARY ANSWER
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.
WHAT IS KNOWN ALREADY
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).
STUDY DESIGN, SIZE, DURATION
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.
PARTICIPANTS/MATERIALS, SETTING, METHODS
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.
MAIN RESULTS AND THE ROLE OF CHANCE
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).
LIMITATIONS, REASONS FOR CAUTION
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.
WIDER IMPLICATIONS OF THE FINDINGS
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.
STUDY FUNDING/COMPETING INTEREST(S)
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.
نبذة عن البحث: يعد العقم الهاجس الأكبر عند النساء المتزوجات وخصوصا عند التقدم في العمر. كما أن قلة الخصوبة لدى عامة النساء آخذة بالأزدياد في الأونة الأخيرة ولعدة أسباب. أحدى هذه االسباب هي تقدم العمر وما يطرأ على التغيير البايولوجي في بيوض الأناث مما يؤدي الى عقم أولي او ثانوي. تعد عضيات المايتوكوندريا الموجودة في البيوض هي بيوت الطاقة التي تنفرد بيها النساء بكميات هائلة مقارنة بالرجال و وجد الباحثون أن الخلل في بيوت الطاقة يقود الى مشاكل في تأخر الإنجاب او الى العقم الدائم. لذا ركزت هذه الدراسة على أستخدام مستهدفات المايتوكوندريا في عكس التأثير السلبي لعامل تقدم العمر وتحسين وظائف المايتوكوندريا في البيوض من خلال زيادة نشاط المايتوكوندريا ومحاربة الجذور الحرة التي تؤدي الى خلل بايلوجي في تركيب المغزل الأنتصافي وأنشطار الكروموسومات في المراحل الجنيني الاولى. خلصت الدراسة الى أن MitoQ و 15BGP يحسنان وظائف المايتوكوندريا في بيوض أناث الفئران المسنة و في بيوض النساء العقيمات مما يزيد من معدلات الخصوبة والإنتاج.