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Alexandra Amaral, Bárbara Lourenço, Mónica Marques, and João Ramalho-Santos

Although mitochondria are best known for being the eukaryotic cell powerhouses, these organelles participate in various cellular functions besides ATP production, such as calcium homoeostasis, generation of reactive oxygen species (ROS), the intrinsic apoptotic pathway and steroid hormone biosynthesis. The aim of this review was to discuss the putative roles of mitochondria in mammalian sperm function and how they may relate to sperm quality and fertilisation ability, particularly in humans. Although paternal mitochondria are degraded inside the zygote, sperm mitochondrial functionality seems to be critical for fertilisation. Indeed, changes in mitochondrial integrity/functionality, namely defects in mitochondrial ultrastructure or in the mitochondrial genome, transcriptome or proteome, as well as low mitochondrial membrane potential or altered oxygen consumption, have been correlated with loss of sperm function (particularly with decreased motility). Results from genetically engineered mouse models also confirmed this trend. On the other hand, increasing evidence suggests that mitochondria derived ATP is not crucial for sperm motility and that glycolysis may be the main ATP supplier for this particular aspect of sperm function. However, there are contradictory data in the literature regarding sperm bioenergetics. The relevance of sperm mitochondria may thus be associated with their role in other physiological features, particularly with the production of ROS, which in controlled levels are needed for proper sperm function. Sperm mitochondria may also serve as intracellular Ca2 + stores, although their role in signalling is still unclear.

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Mónica Marques, Ana Paula Sousa, Artur Paiva, Teresa Almeida-Santos, and João Ramalho-Santos

We have applied the mitochondria-specific superoxide fluorescent probe MitoSOX Red (MitoSOX) to detect mitochondria-specific reactive oxygen species (mROS) production in human sperm samples using flow cytometry. We show that human ejaculates are heterogeneous in terms of mROS production, with three subpopulations clearly detectable, comprising sperm that produce increasing amounts of mROS (MitoSOX−, MitoSOX+, and MitoSOX++). The sperm subpopulation producing the lowest amount of mROS represented the most functional subset of male gametes within the ejaculate, as it was correlated with the highest amount of live and non-apoptotic sperm and increased both in samples with better semen parameters and in samples processed by both density-gradient centrifugation and swim-up, both known to select for higher quality sperm. Importantly, the MitoSOX− subpopulation was clearly more prevalent in samples that gave rise to pregnancies following assisted reproduction. Our work, therefore, not only describe discreet human sperm heterogeneity at the mROS level but also suggests that mROS may represent a strategy to both evaluate sperm samples and isolate the most functional gametes for assisted reproduction.

Free Portuguese abstract

A Portuguese translation of this abstract is freely available at

Free access

Andreia Filipa Silva, João Ramalho-Santos, and Sandra Amaral

Immune infertility occurs due to the presence of antisperm antibodies (ASA). This type of infertility has a relatively low prevalence (2.6–6.6% in infertile men), and its etiology, risk factors, targets, and consequences for male fertility are not completely understood. While it is largely accepted that abnormalities in the blood–testis barrier and/or blood–epididymal barrier are the main factors behind its etiology, and that sperm motility is the most frequently reported altered parameter, few are the well-defined risk factors and ASA targets only now started to be disclosed, with proteins involved in sperm–oocyte interaction rising as the most significant. The development of potential treatments is also limited, being the corticosteroids the more promising. Overall, there are still many knowledge gaps related to immune infertility. With this review, we aimed to gather all the information collected from studies developed in humans in the last decade. Despite the controversial results/inconsistencies, that are not only a result of the complexity of mechanisms/variables involved in ASA infertility but also from the technical approaches to assess ASA and the lack of a consensus regarding the thresholds to be used, this manuscript aims to bring a fresh update on the field. It has become clear that, to obtain more/reliable data, there is a need to assess ASA in all the routine seminal analyses, following WHO recommendations. In this way, it will be possible to obtain consistent and comparable information, that can add to current knowledge. Additionally, multicentric studies with large cohorts are also missing, and future research should take this into consideration.

Free access

Bibiana Correia, Maria Inês Sousa, and João Ramalho-Santos

Reproduction depends on many factors, from gamete quality to placenta formation, to fetal development. The mTOR pathway is emerging as a major player that integrates several cellular processes in response to a variety of environmental cues that are relevant in many aspects of reproduction. This review provides a general overview, summarizing the involvement of the two mTOR complexes (mTORC1 and mTORC2) in integrating signaling pathways, sensing environmental status, and managing physiological processes inherent to successful reproductive outcomes and pluripotent stem cell function. As a well-known governor of multiple cellular functions, it is not surprising that mTOR has a key regulatory role in determining cell quiescence or differentiation. In the gonads mTOR helps maintain spermatogonial stem cell and follicle identity and tightly regulates differentiation in both systems to ensure proper gamete production. The mTOR pathway is also known to prevent premature follicle exhaustion, while also controlling the blood–testis barrier in the male gonad. In stem cells mTOR again seems to have a role in controlling both pluripotency and differentiation, mirrored by its in vivo roles in the embryo, notably in regulating diapause. Finally, although there are clearly more complex systems intertwined in placental function, mTOR seems to serve as an early checkpoint for development progression and successful implantation.

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Ana Filipa Ferreira, Maria Soares, Sandra Almeida Reis, João Ramalho-Santos, Ana Paula Sousa, and Teresa Almeida-Santos

Mitochondrial supplementation was proposed as a complementary treatment to assisted reproductive technologies to improve oocyte competence and support post-fertilization development. This strategy is based on the fact that poor-quality/aged oocytes contain lower and dysfunctional mitochondria. However, the efficacy and safety of mitochondrial supplementation are still controversial. Therefore, this review summarizes the clinical/biological outcomes of mitochondrial supplementation, aiming to improve oocyte competence or explore the safety of this technique, and was based on an online search using PubMed and Web of Science, until September 2019. The studies included reported outcomes related to the efficacy and safety of mitochondrial supplementation either in human or animal models (bovine, porcine and mouse). Extracted data were organized according to study objective, the mitochondrial source and the main outcomes: fertilization/pregnancy rates, embryo development and adverse outcomes. Clinical pregnancy was not improved in the only randomized controlled trial published, although an increase was demonstrated in other non-randomized studies. Fertilization rate and embryo development were not different from control groups in the majority of studies, although performed in different contexts and using diverse sources of mitochondria. The safety of mitochondria transfer is still a concern, however, the euploid rate and the absence of reported congenital malformation from the clinical studies are reassuring. In summary, mitochondrial supplementation does not seem to cause harm although the benefit of improving oocyte competence is still unclear due to the diversity of methodological approaches and low-quality of the data available. Analyzed data support the need to investigate further, in both pre-clinical and clinical contexts.