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Mitochondrial DNA removal is essential for sperm development and activity

ABSTRACT: Active 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 sperm mtDNA removal is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a novel mitochondrial exonuclease, Poldip2, that is specially 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 to prevent potential nuclear-mito imbalance in mature sperm, in which nuclear genome activity is shut down.

ORGANISM(S): Drosophila melanogaster (fruit fly)

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PROVIDER: S-BSST1809 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Study questionAre sperm mitochondrial DNA copy number (mtDNAcn) and deletion rate (mtDNAdel) associated with odds of fertilization and high embryo quality at Days 3 and 5?Summary answerHigher sperm mtDNAcn and mtDNAdel were associated with lower odds of high quality Day 3 embryos and transfer quality Day 5 embryos, both of which were primarily driven by lowered odds of fertilization.What is known alreadySperm mtDNAcn and mtDNAdel have been previously associated with poor semen parameters and clinical male infertility. One prior study has shown that mtDNAdel is associated with lower fertilization rates. However, it is unknown whether these characteristics are linked with ART outcomes.Study design, size, durationThis prospective observational study included 119 sperm samples collected from men undergoing ART in Western Massachusetts. ART outcomes were observed through to Day 5 post-insemination.Participants/materials, settings, methodsAs part of the Sperm Environmental Epigenetics and Development Study (SEEDS), 119 sperm samples were collected from men undergoing ART in Western Massachusetts. Sperm mtDNAcn and mtDNAdel were measured via triplex probe-based qPCR. Fertilization, Day 3 embryo quality and Day 5 embryo quality measures were fitted with mtDNAcn and mtDNAdel using generalized estimating equations.Main results and the role of chanceAfter adjusting for male age and measurement batches, higher sperm mtDNAcn and mtDNAdel were associated with lower odds of fertilization (P = 0.01 and P < 0.01), high quality Day 3 embryos (P = 0.02 for both) and transfer quality Day 5 embryos (P = 0.01 and P = 0.09). However, the associations of mtDNAcn and mtDNAdel with Day 3 high quality status and Day 5 transfer quality status were attenuated in models restricted to fertilized oocytes. Sperm mtDNAcn and mtDNAdel remained statistically significant in models adjusted for both male age and semen parameters, although models including both mtDNA markers generally favoured mtDNAdel.Limitations, reasons for cautionOur sample only included oocytes and embryos from 119 couples and thus large diverse cohorts are necessary to confirm the association of sperm mtDNA biomarkers with embryo development.Wider implications of the findingsTo our knowledge, our study is the first to assess the associations of sperm mtDNAcn and mtDNAdel with fertilization and embryo quality. The biological mechanism(s) underlying these associations are unknown. Multivariable models suggest that sperm mtDNAcn and mtDNAdel provide discrimination independent of age and semen parameters; therefore, future investigation of the utility of sperm mtDNA as a biomarker for ART outcomes is warranted.Study funding/competing interest(s)This work was supported by Grant (K22-ES023085) from the National Institute of Environmental Health Sciences. The authors declare no competing interests.Trial registration numberN/A.

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Mitochondrial DNA removal is essential for sperm development and activity

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