Mitochondrial enrichment in infertile patients: a review of differentmitochondrial replacement therapies

Cristina Rodríguez-Varela; Sonia Herraiz; Elena Labarta

摘要

Poor ovarian responders exhibit a quantitative reduction in their follicularpool, and most cases are also associated with poor oocyte quality due topatient’s age, which leads to impaired in vitro fertilisationoutcomes. In particular, poor oocyte quality has been related to mitochondrialdysfunction and/or low mitochondrial count as these organelles are crucial inmany essential oocyte processes. Therefore, mitochondrial enrichment has beenproposed as a potential therapy option in infertile patients to improve oocytequality and subsequent in vitro fertilisation outcomes.Nowadays, different options are available for mitochondrial enrichmenttreatments that are encompassed in two main approaches: heterologous andautologous. In the heterologous approach, mitochondria come from an externalsource, which is an oocyte donor. These techniques include transferring either aportion of the donor’s oocyte cytoplasm to the recipient oocyte or nuclearmaterial from the patient to the donor’s oocyte. In any case, this approachentails many ethical and safety concerns that mainly arise from the uncertaindegree of mitochondrial heteroplasmy deriving from it. Thus the autologousapproach is considered a suitable potential tool to improve oocyte quality byovercoming the heteroplasmy issue. Autologous mitochondrial transfer, however,has not yielded as many beneficial outcomes as initially expected. Proposedmitochondrial autologous sources include immature oocytes, granulosa cells,germline stem cells, and adipose-derived stem cells. Presently, it would seemthat these autologous techniques do not improve clinical outcomes in humaninfertile patients. However, further trials still need to be performed toconfirm these results. Besides these two main categories, new strategies havearisen for oocyte rejuvenation by improving patient’s own mitochondrial functionand avoiding the unknown consequences of third-party genetic material. This isthe case of antioxidants, which may enhance mitochondrial activity bycounteracting and/or preventing oxidative stress damage. Among others,coenzyme-Q10 and melatonin have shown promising results in low-prognosisinfertile patients, although further randomised clinical trials are stillnecessary. Keywords: mitochondria, mitochondrial enrichment, oocyte rejuvenation, poor oocyte qualityIntroductionOvarian ageing is one of the main causes of infertility in poor ovarian responders(POR), along with genetic or physiological factors (such as obesity and geneticpolymorphisms affecting gonadotropin receptors), which can alter women’sresponsiveness to ovarian stimulation.~(1) Ovarian ageing, regardless of it being premature or physiological, reducesthe ovarian reserve, characterised by a quantitative and qualitative alteration of oocytes.~(2) Hence this condition results in not only poor response to ovarianstimulation, but also in poor oocyte quality, especially in those POR of advancedmaternal age. This in turn cuts pregnancy chances by in vitro fertilisation (IVF) techniques.~(3)In particular, poor oocyte quality is characterised by impaired nuclear and/orcytoplasmic maturity. It has been recently related to either mitochondrialdysfunction or low mitochondrial count as these organelles are crucial for acquiringoocyte competence. These two conditions are also associated with the ageing process.On one hand, mtDNA mutations accumulate over time, insofar as a higher mtDNAmutation rate present in aged oocytes may cause their mitochondrial dysfunction.~(2) On the other hand, as a measure of mitochondrial content, low mitochondrialDNA (mtDNA) levels have been found in aged oocytes from not only advanced maternalage but also from diminished ovarian reserve patients compared to oocytes from womenwith normal ovarian reserves.~(4)Mitochondria are the powerhouse organelles of cells, as they are the main source ofenergy that comes in the form of adenosine triphosphate (ATP). This molecule isessential in oocytes for successful meiotic spindle assembly, proper chromosomesegregation, maturation, fertilisation, and subsequent pre-implantationembryogenesis. Mitochondria also play a role in Ca~(2+) homeostasis,apoptosis regulation, and management of the oxidative stress, which are crucialprocesses for proper fertilisation and embryo development.~(5) Consequently, an alteration of these mechanisms could compromise oocytequality and further embryo development. Indeed, low ATP content has been related toincreased fertilisation failure, arrested division, and abnormal embryo developmentin infertile patients.~(6)Hence an optimal number of functional mitochondria are crucial to acquire oocytecompetence but also for proper blastomere survival in the developing embryo.~(7) However, mitochondrial replication is inhibited during embryo development.~(8) One plausible explanation may be to keep mtDNA mutations at a minimum, givenits high exposure to free radicals, along with its poor genomic repair andprotective mechanisms compared to nuclear genet

机译：卵巢响应者可怜的卵巢响应者对其毛囊池进行定量减少，大多数病例也与卵母细胞质量较差的越峰的年龄相关，这导致体外施肥不受损害。特别地，卵母细胞质量差与线粒体功能障碍和/或低线粒体计数有关，因为这些细胞器是至关重要的必要卵母细胞过程。因此，线粒体富集被威胁作为不孕患者的潜在治疗选择，以改善卵核效应和随后的体外施肥效应。目前，不同的选择可用于两种主要方法的线粒体富集特征：异源和异教。在异源方法中，线粒体来自外部源，即卵母节。这些技术包括将供体的卵母细胞细胞质的永磁毛细胞转移到受体卵母细胞或从患者到供体的卵母细胞的核材料。在任何情况下，这种方法都是许多伦理和安全问题，主要是从IT衍生的线粒体异质的不确定regleree。因此，AutologouseApproach被认为是一种适当的潜在工具，以改善卵母细胞质量植入异质问题。然而，自体的线粒体转移尚未产生最初预期的许多有益的结果。 ProtoSmitochondrial自体源包括未成熟的卵母细胞，颗粒细胞，种系干细胞和脂肪衍生的干细胞。目前，似乎这些自体技术不会改善人素患者的临床结果。但是，需要进行进一步的试验，以便对这些结果进行确认。除了这两个主要类别，通过改善患者自己的线粒体功能和避免第三方遗传物质的未知后果，新的策略是针对卵母细胞的恢复活力。这是抗氧化剂的情况，其可以增强线粒体活性，通过应安排和/或预防氧化应激损伤。除此之外，辅酶-Q10和褪黑激素表明了低预测患者的有希望的结果，尽管有必要进一步随机临床试验。关键词：线粒体，线粒体富集，卵母细胞恢复活力，卵母细胞QualityIntrodultovian老龄化是卵巢伴者（POR）中不孕症的主要原因之一，以及遗传或生理因素（例如影响促性腺激素受体的肥胖和遗传症状），可以改变妇女的卵巢刺激。〜（1）卵巢老化，无论它过早或生理，Reducesthe卵巢储备，都是通过卵母细胞的定量和定性改变。因此，这种情况不仅导致对较差的反应卵巢刺激，但也处于卵母细胞质量差，尤其是在那些晚期的治疗症的POR中。这反过来通过体外施肥（IVF）技术来减少妊娠机理。〜（3）特别地，卵母细胞质量差的特点是核和/或单独的成熟性受损。它最近与线粒体功能障碍或低线粒体计数相关，因为这些细胞器对血液细胞能力至关重要。这两个条件也与老化过程有关。一方面，MTDNA突变随着时间的推移积累，只要在老年的卵母细胞中存在的更高的MTD表现率可能导致它们的线粒体功能障碍。另一方面，〜（2）另一方面来自不仅从卵巢储备患者的卵巢储备患者的老年卵母细胞中发现了低线粒体含量，低线粒体含量，低卵母细胞，而且与卵巢储备的卵母细胞相比，来自卵巢储备的卵巢蛋白。〜（4）线粒体是细胞的动力室细胞器是腺苷三磷酸腺苷（ATP）形式的主要来源。该分子在卵母细胞中是成功的减数纺锤组件，适当的染色体测定，成熟，施肥和随后的预植物预造型。线粒体也在Ca〜（2+）稳态，细胞凋亡调节和氧化应激管理中发挥作用，这是适当施肥和胚胎发育的关键过程。〜（5）因此，这些机制的改变可能会损害卵肾上腺梗死和进一步胚胎发展。实际上，低ATP含量已与毒素有关的施肥失败，被捕分裂和异常胚胎发育患者。〜（6）因此，功能性线粒体的最佳数量至关重要，以获得卵细胞菌，而且在发育中胚胎中适当的卵泡生存率是至关重要的。〜（7）然而，在胚胎发育期间抑制了线粒体复制。〜（8）一种可合理的解释可以是最小的，使MTDNA突变保持高暴露于自由基，以及与核群体相比的较差的基因组修复和保护机制。

Mitochondrial enrichment in infertile patients: a review of differentmitochondrial replacement therapies

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