Mitochondrial DNA alteration in male infertility

L’infertilité concerne plus de 50 millions de couples dans le monde et le facteur masculin est incriminé dans 50% des cas. Les mitochondries sont reconnues comme essentielles aux spermatozoïdes, notamment pour la motilité flagellaire, la capacitation, la réaction acrosomique et la fusion gamétique. L’altération des fonctions mitochondriales pourraient être liées à la baisse de la qualité du sperme et à l’infertilité. L’objectif principal de ce travail était d’approfondir nos connaissances sur le lien entre le génome mitochondrial des spermatozoïdes et l’infertilité masculine, mais aussi d’évaluer l’environnement métabolique des spermatozoïdes en cas d’altération des paramètres spermatiques. Nous avons mis en évidence, avec le séquençage haut débit, une fréquence de grands réarrangements plus importante dans l’ADNmt les spermatozoïdes de meilleure qualité, parallèlement à la diminution significative de leur taux d'ADNmt. Nous pensons que cette découverte est le résultat d'un phénomène physiologique d'élimination active de l'ADNmt paternel dans les spermatozoïdes contribuant à la transmission uniparentale maternelle de l'ADNmt. L’étude métabolomique du liquide séminal nous a permis d’obtenir un aperçu global des défauts métaboliques contribuant à l'altération structurelle et fonctionnelle des spermatozoïdes dans l'oligoasthénospermie sévère. Ces résultats offrent de nouvelles perspectives sur la compréhension de l'infertilité masculine qui pourraient aider à développer des outils diagnostiques et de futurs traitements spécifiques.Infertility affects more than 50 million couples worldwide and the male factor is involved in 50% of cases. Mitochondria are known to be essential for spermatozoa, including flagellar motility, capacitation, acrosome reaction and gametic fusion. Impaired mitochondrial function could be linked to decreased sperm quality and infertility. The main objective of this work was to improve our knowledge of the link between the mitochondrial genome of spermatozoa and male infertility, but also to evaluate the metabolic environment of spermatozoa in case of altered sperm parameters. We found, with high-throughput sequencing, a higher frequency of large rearrangements in the mtDNA of higher quality sperm, in parallel with a significant decrease in their mtDNA content. We believe that this finding is the result of a physiological phenomenon of active removal of paternal mtDNA in spermatozoa contributing to maternal uniparental transmission of mtDNA. The metabolomic study of seminal plasma allowed us to obtain a comprehensive overview of the metabolic defects contributing to the structural and functional alteration of spermatozoa in severe oligoasthenospermia. These results offer new insights into the understanding of male infertility that may help to develop diagnostic tools and specific future treatments

L’altération de l’ADN mitochondrial dans l’infertilité masculine

Infertility affects more than 50 million couples worldwide and the male factor is involved in 50% of cases. Mitochondria are known to be essential for spermatozoa, including flagellar motility, capacitation, acrosome reaction and gametic fusion. Impaired mitochondrial function could be linked to decreased sperm quality and infertility. The main objective of this work was to improve our knowledge of the link between the mitochondrial genome of spermatozoa and male infertility, but also to evaluate the metabolic environment of spermatozoa in case of altered sperm parameters. We found, with high-throughput sequencing, a higher frequency of large rearrangements in the mtDNA of higher quality sperm, in parallel with a significant decrease in their mtDNA content. We believe that this finding is the result of a physiological phenomenon of active removal of paternal mtDNA in spermatozoa contributing to maternal uniparental transmission of mtDNA. The metabolomic study of seminal plasma allowed us to obtain a comprehensive overview of the metabolic defects contributing to the structural and functional alteration of spermatozoa in severe oligoasthenospermia. These results offer new insights into the understanding of male infertility that may help to develop diagnostic tools and specific future treatments.L’infertilité concerne plus de 50 millions de couples dans le monde et le facteur masculin est incriminé dans 50% des cas. Les mitochondries sont reconnues comme essentielles aux spermatozoïdes, notamment pour la motilité flagellaire, la capacitation, la réaction acrosomique et la fusion gamétique. L’altération des fonctions mitochondriales pourraient être liées à la baisse de la qualité du sperme et à l’infertilité. L’objectif principal de ce travail était d’approfondir nos connaissances sur le lien entre le génome mitochondrial des spermatozoïdes et l’infertilité masculine, mais aussi d’évaluer l’environnement métabolique des spermatozoïdes en cas d’altération des paramètres spermatiques. Nous avons mis en évidence, avec le séquençage haut débit, une fréquence de grands réarrangements plus importante dans l’ADNmt les spermatozoïdes de meilleure qualité, parallèlement à la diminution significative de leur taux d'ADNmt. Nous pensons que cette découverte est le résultat d'un phénomène physiologique d'élimination active de l'ADNmt paternel dans les spermatozoïdes contribuant à la transmission uniparentale maternelle de l'ADNmt. L’étude métabolomique du liquide séminal nous a permis d’obtenir un aperçu global des défauts métaboliques contribuant à l'altération structurelle et fonctionnelle des spermatozoïdes dans l'oligoasthénospermie sévère. Ces résultats offrent de nouvelles perspectives sur la compréhension de l'infertilité masculine qui pourraient aider à développer des outils diagnostiques et de futurs traitements spécifiques

Embryo and Its Mitochondria

International audienceThe mitochondria, present in almost all eukaryotic cells, produce energy but also contribute to many other essential cellular functions. One of the unique characteristics of the mitochondria is that they have their own genome, which is only maternally transmitted via highly specific mechanisms that occur during gametogenesis and embryogenesis. The mature oocyte has the highest mitochondrial DNA copy number of any cell. This high mitochondrial mass is directly correlated to the capacity of the oocyte to support the early stages of embryo development in many species. Indeed, the subtle energetic and metabolic modifications that are necessary for each of the key steps of early embryonic development rely heavily on the oocyte’s mitochondrial load and activity. For example, epigenetic reprogramming depends on the metabolic cofactors produced by the mitochondrial metabolism, and the reactive oxygen species derived from the mitochondrial respiratory chain are essential for the regulation of cell signaling in the embryo. All these elements have also led scientists to consider the mitochondria as a potential biomarker of oocyte competence and embryo viability, as well as a key target for future potential therapies. However, more studies are needed to confirm these findings. This review article summarizes the past two decades of research that have led to the current understanding of mitochondrial functions in reproduction

Cancer/Testis Antigens into mitochondria: a hub between spermatogenesis, tumorigenesis and mitochondrial physiology adaptation

International audienceCancer/Testis Antigens (CTAs) genes are expressed only during spermatogenesis and tumorigenesis. Both processes share common specific metabolic adaptation related to energy supply, with a glucose to lactate gradient, leading to changes in mitochondrial physiology paralleling CTAs expression. In this review, we address the role of CTAs in mitochondria (mitoCTAs), by reviewing all published data, and assessing the putative localization of CTAs by screening for the presence of a mitochondrial targeting sequence (MTS). We evidenced that among the 276 CTAs, five were already shown to interfere with mitochondrial activities and 67 display a potential MTS

A Metabolomic Profile of Seminal Fluid in Extremely Severe Oligozoopermia Suggesting an Epididymal Involvement

Male infertility has increased in the last decade. Pathophysiologic mechanisms behind extreme oligospermia (EO) are not yet fully understood. In new “omics” approaches, metabolomic can offer new information and help elucidate these mechanisms. We performed a metabolomics study of the seminal fluid (SF) in order to understand the mechanisms implicated in EO. We realized a targeted quantitative analysis using high performance liquid chromatography and mass spectrometry to compare the SF metabolomic profile of 19 men with EO with that of 22 men with a history of vasectomy (V) and 20 men with normal semen parameters (C). A total of 114 metabolites were identified. We obtained a multivariate OPLS-DA model discriminating the three groups. Signatures show significantly higher levels of amino acids and polyamines in C group. The sum of polyunsaturated fatty acids and free carnitine progressively decrease between the three groups (C > EO > V) and sphingomyelins are significantly lower in V group. Our signature characterizing EO includes metabolites already linked to infertility in previous studies. The similarities between the signatures of the EO and V groups are clear evidence of epididymal dysfunction in the case of testicular damage. This study shows the complexity of the metabolomic dysfunction occurring in the SF of EO men and underlines the importance of metabolomics in understanding male infertility

Metabolomic signature of the seminal plasma in men with severe oligoasthenospermia

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Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations

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Oligogenic heterozygous inheritance of sperm abnormalities in mouse

Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man

PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

Abstract The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA‐binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA regulators) suggest an original role for Patl2 in mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2−/− animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans