Mitochondria are multitasking organelles involved in ATP synthesis, reactive oxygen species (ROS) production, calcium signalling and apoptosis; and mitochondrial defects are known to cause physiological dysfunction, including infertility. The goal of this review was to identify and discuss common themes in mitochondrial function related to mammalian reproduction. The scientific literature was searched for studies reporting on the several aspects of mitochondrial activity in mammalian testis, sperm, oocytes, early embryos and embryonic stem cells. ATP synthesis and ROS production are the most discussed aspects of mitochondrial function. Metabolic shifts from mitochondria-produced ATP to glycolysis occur at several stages, notably during gametogenesis and early embryo development, either reflecting developmental switches or substrate availability. The exact role of sperm mitochondria is especially controversial. Mitochondria-generated ROS function in signalling but are mostly described when produced under pathological conditions. Mitochondria-based calcium signalling is primarily important in embryo activation and embryonic stem cell differentiation. Besides pathologically triggered apoptosis, mitochondria participate in apoptotic events related to the regulation of spermatogonial cell number, as well as gamete, embryo and embryonic stem cell quality. Interestingly, data from knock-out (KO) mice is not always straightforward in terms of expected phenotypes. Finally, recent data suggests that mitochondrial activity can modulate embryonic stem cell pluripotency as well as differentiation into distinct cellular fates. Mitochondria-based events regulate different aspects of reproductive function, but these are not uniform throughout the several systems reviewed. Low mitochondrial activity seems a feature of ‘stemness’, being described in spermatogonia, early embryo, inner cell mass cells and embryonic stem cells.

Diabetes Mellitus (DM), a state of chronic hyperglycemia, is a major cause of serious micro and macrovascular diseases, affecting, therefore, nearly every system in the body. Growing evidence indicates that oxidative stress is increased in diabetes due to overproduction of reactive oxygen species (ROS) and decreased efficiency of antioxidant defences, a process that starts very early and worsens over the course of the disease. During the development of diabetes, oxidation of lipids, proteins and DNA increase with time. Mitochondrial DNA mutations have also been reported in diabetic tissues, suggesting oxidative stress-related mitochondrial damage. Diabetes- related oxidative stress may also be the trigger for many alterations on sexual function, which can also include decreased testicular mitochondrial function. Although sexual disorders have been extensively studied in diabetic men, possible changes in the sexual function of diabetic women have only recently received attention. The prevalence of sexual dysfunction in diabetic men approaches 50%, whereas in diabetic women it seems to be slightly lower. Testicular dysfunction, impotence, decreased fertility potential and retrograde ejaculations are conditions that have been described in diabetic males. Diabetes is also the most common cause of erectile dysfunction in men. Poor semen quality has also been reported in diabetic men, including decreased sperm motility and concentration, abnormal morphology and increased seminal plasma abnormalities. In addition, diabetic men may have decreased serum testosterone due to impaired Leydig cell function. Among diabetic women neuropathy, vascular impairment and psychological complaints have been implicated in the pathogenesis of decreased libido, low arousability, decreased vaginal lubrication, orgasmic dysfunction, and dyspareunia. An association between the production of excess radical oxygen species and disturbed embryogenesis in diabetic pregnancies has also been suggested. In fact, maternal diabetes during pregnancy is associated with an increased risk of complications in the offspring, such as altered fetal growth, polyhydramnios, fetal loss and congenital malformations. In addition, hypocalemia and reduced bone mineral content are found in neonates of diabetic mothers. Abnormalities in gametogenesis and sexual function have also been documented in animal models for both types of Diabetes, which thus constitute an important research tool to both study the effects of the disease, and to test novel therapeutical interventions. Because sexuality and fertility are important aspects in the lives of individuals and couples, and considering that over 124 million individuals worldwide suffer from Diabetes, this review highlights the impact of Diabetes and associated oxidative stress on sexual function.

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.

Researching the effects of aging in the male reproductive system is not trivial. Not only are multiple changes at molecular, cellular and endocrine levels involved, but any findings must be discussed with variable individual characteristics, as well as with lifestyle and environmental factors. Age-related changes in the reproductive system include any aspect of reproductive function, from deregulation of the hypothalamic-pituitary- gonadal axis and of local auto/paracrine interactions, to effects on testicular stem cells, defects in testicular architecture and spermatogenesis, or sperm with decreased functionality. Several theories place mitochondria at the hub of cellular events related to aging, namely regarding the accumulation of oxidative damage to cells and tissues, a process in which these organelles play a prominent role, although alternative theories have also emerged. However, oxidative stress is not the only process involved in mitochondrial-related aging; mitochondrial energy metabolism, changes in mitochondrial DNA or in mitochondrial-dependent testosterone production are also important. Crucially, all these issues are likely interdependent. We will review evidence that suggests that mitochondria constitute a common link between aging and fertility loss.