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Mitochondrial DNA removal is essential for sperm development and activity

ABSTRACT: Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear-genome activity is shut down.

SUBMITTER: Hong Xu

PROVIDER: S-SCDT-10_1038-S44318-025-00377-5 | biostudies-other |

REPOSITORIES: biostudies-other

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Mitochondrial DNA removal is essential for sperm development and activity.

Project description:Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear genome activity is shut down.

| S-EPMC11914152 | biostudies-literature

Mitochondrial DNA removal is essential for sperm development and activity

Project description: Not available

| S-BSST1809 | biostudies-other

Barriers to male transmission of mitochondrial DNA in sperm development.

Project description:Across the eukaryotic phylogeny, offspring usually inherit their mitochondrial genome from only one of two parents: in animals, the female. Although mechanisms that eliminate paternally derived mitochondria from the zygote have been sought, the developmental stage at which paternal transmission of mitochondrial DNA is restricted is unknown in most animals. Here, we show that the mitochondria of mature Drosophila sperm lack DNA, and we uncover two processes that eliminate mitochondrial DNA during spermatogenesis. Visualization of mitochondrial DNA nucleoids revealed their abrupt disappearance from developing spermatids in a process requiring the mitochondrial nuclease, Endonuclease G. In Endonuclease G mutants, persisting nucleoids are swept out of spermatids by a cellular remodeling process that trims and shapes spermatid tails. Our results show that mitochondrial DNA is eliminated during spermatogenesis, thereby removing the capacity of sperm to transmit the mitochondrial genome to the next generation.

| S-EPMC3306594 | biostudies-literature

Sperm function, mitochondrial activity and in vivo fertility are associated to their mitochondrial DNA content in pigs.

Project description:BackgroundDespite their low abundance in sperm, mitochondria have diverse functions in this cell type, including energy production, signalling and calcium regulation. In humans, sperm mitochondrial DNA content (mtDNAc) has been reported to be negatively linked to sperm function and fertility. Yet, the association between mtDNAc and sperm function in livestock remains unexplored. For this reason, this study aimed to shed some light on the link between mtDNAc and sperm function and fertilising potential in pigs. A qPCR method for mtDNAc quantification was optimised for pig sperm, and the association of this parameter with sperm motility, kinematics, mitochondrial activity, and fertility was subsequently interrogated.ResultsFirst, the qPCR method was found to be sensitive and efficient for mtDNAc quantification in pig sperm. By using this technique, mtDNAc was observed to be associated to sperm motility, mitochondrial activity and in vivo, but not in vitro, fertility outcomes. Specifically, sperm with low mtDNAc were seen to exhibit greater motility but decreased mitochondrial activity and intracellular reactive oxygen species. Interestingly, samples with lower mtDNAc showed higher conception and farrowing rates, but similar in vitro fertilisation rates and embryo development, when compared to those with greater mtDNAc.ConclusionsThese findings enrich our comprehension of the association of mtDNAc with sperm biology, and lay the foundation for future research into employing this parameter as a molecular predictor for sperm function and fertility in livestock.

| S-EPMC10832242 | biostudies-literature

Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.

Project description:The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells.

| S-EPMC3383994 | biostudies-literature

C. elegans ATAD-3 is essential for mitochondrial activity and development.

Project description:BackgroundMammalian ATAD3 is a mitochondrial protein, which is thought to play an important role in nucleoid organization. However, its exact function is still unresolved.ResultsHere, we characterize the Caenorhabditis elegans (C. elegans) ATAD3 homologue (ATAD-3) and investigate its importance for mitochondrial function and development. We show that ATAD-3 is highly conserved among different species and RNA mediated interference against atad-3 causes severe defects, characterized by early larval arrest, gonadal dysfunction and embryonic lethality. Investigation of mitochondrial physiology revealed a disturbance in organellar structure while biogenesis and function, as indicated by complex I and citrate synthase activities, appeared to be unaltered according to the developmental stage. Nevertheless, we observed very low complex I and citrate synthase activities in L1 larvae populations in comparison to higher larval and adult stages. Our findings indicate that atad-3(RNAi) animals arrest at developmental stages with low mitochondrial activity. In addition, a reduced intestinal fat storage and low lysosomal content after depletion of ATAD-3 suggests a central role of this protein for metabolic activity.ConclusionsIn summary, our data clearly indicate that ATAD-3 is essential for C. elegans development in vivo. Moreover, our results suggest that the protein is important for the upregulation of mitochondrial activity during the transition to higher larval stages.

| S-EPMC2765634 | biostudies-literature

Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility.

Project description:Mitochondrial health is crucial to sperm quality and male fertility, but the precise role of mitochondria in sperm function remains unclear. SDHA is a component of the succinate dehydrogenase (SDH) complex and plays a critical role in mitochondria. In humans, SDH activity is positively correlated with sperm quality, and mutations in SDHA are associated with Leigh Syndrome. Here we report that the C. elegans SDHA orthologue SDHA-2 is essential for male fertility: sdha-2 mutants produce dramatically fewer offspring due to defective sperm activation and motility, have hyperfused sperm mitochondria, and disrupted redox balance. Similar sperm motility defects in sdha-1 and icl-1 mutant animals suggest an imbalance in metabolites may underlie the fertility defect. Our results demonstrate a role for SDHA-2 in sperm motility and male reproductive health and establish an animal model of SDH deficiency-associated infertility.

| S-EPMC9709242 | biostudies-literature

Sperm DNA Fragmentation and Sperm-Borne miRNAs: Molecular Biomarkers of Embryo Development?

Project description:The evaluation of morpho-functional sperm characteristics alone is not enough to explain infertility or to predict the outcome of Assisted Reproductive Technologies (ART): more sensitive diagnostic tools are needed in clinical practice. The aim of the present study was to analyze Sperm DNA Fragmentation (SDF) and sperm-borne miR-34c-5p and miR-449b-5p levels in men of couples undergoing ART, in order to investigate any correlations with fertilization rate, embryo quality and development. Male partners (n = 106) were recruited. Semen analysis, SDF evaluation and molecular profiling analysis of miR-34c-5p and miR-449b-5p (in 38 subjects) were performed. Sperm DNA Fragmentation evaluation- a positive correlation between SDF post sperm selection and the percentage of low-quality embryos and a negative correlation with viable embryo were found. SDF > 2.9% increased the risk of obtaining a non-viable embryo by almost 4-fold. Sperm miRNAs profile-we found an association with both miRNAs and sperm concentration, while miR-449b-5p is positively associated with SDF. Moreover, the two miRNAs are positively correlated. Higher levels of miR-34c-5p compared to miR-449b-5p increases by 14-fold the probability of obtaining viable embryos. This study shows that SDF, sperm miR-34c-5p, and miR-449b-5p have a promising role as biomarkers of semen quality and ART outcome.

| S-EPMC9864861 | biostudies-literature

Embryo development is impaired by sperm mitochondrial-derived ROS.

Project description:BackgroundBasal energetic metabolism in sperm, particularly oxidative phosphorylation, is known to condition not only their oocyte fertilising ability, but also the subsequent embryo development. While the molecular pathways underlying these events still need to be elucidated, reactive oxygen species (ROS) could have a relevant role. We, therefore, aimed to describe the mechanisms through which mitochondrial activity can influence the first stages of embryo development.ResultsWe first show that embryo development is tightly influenced by both intracellular ROS and mitochondrial activity. In addition, we depict that the inhibition of mitochondrial activity dramatically decreases intracellular ROS levels. Finally, we also demonstrate that the inhibition of mitochondrial respiration positively influences sperm DNA integrity, most likely because of the depletion of intracellular ROS formation.ConclusionCollectively, the data presented in this work reveals that impairment of early embryo development may result from the accumulation of sperm DNA damage caused by mitochondrial-derived ROS.

| S-EPMC10825979 | biostudies-literature

Mouse Y-Encoded Transcription Factor Zfy2 Is Essential for Sperm Head Remodelling and Sperm Tail Development.

Project description:A previous study indicated that genetic information encoded on the mouse Y chromosome short arm (Yp) is required for efficient completion of the second meiotic division (that generates haploid round spermatids), restructuring of the sperm head, and development of the sperm tail. Using mouse models lacking a Y chromosome but with varying Yp gene complements provided by Yp chromosomal derivatives or transgenes, we recently identified the Y-encoded zinc finger transcription factors Zfy1 and Zfy2 as the Yp genes promoting the second meiotic division. Using the same mouse models we here show that Zfy2 (but not Zfy1) contributes to the restructuring of the sperm head and is required for the development of the sperm tail. The preferential involvement of Zfy2 is consistent with the presence of an additional strong spermatid-specific promotor that has been acquired by this gene. This is further supported by the fact that promotion of sperm morphogenesis is also seen in one of the two markedly Yp gene deficient models in which a Yp deletion has created a Zfy2/1 fusion gene that is driven by the strong Zfy2 spermatid-specific promotor, but encodes a protein almost identical to that encoded by Zfy1. Our results point to there being further genetic information on Yp that also has a role in restructuring the sperm head.

| S-EPMC4713206 | biostudies-literature

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