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POLDIP2 regulates mtDNA elimination during Drosophila spermatogenesis to ensure maternal inheritance

ABSTRACT: Maternal inheritance of mitochondrial DNA (mtDNA) is highly conserved in metazoans. While many species eliminate paternal mtDNA during late sperm development to foster maternal inheritance, the regulatory mechanisms governing this process remain elusive. Through a forward genetic screen in Drosophila, we identified 47 mutant lines exhibiting substantial retention of mtDNA in mature sperm. We mapped one line to Poldip2, a gene predominantly expressed in the testis. Disruption of Poldip2 led to substantial mtDNA retention in mature sperm and subsequent paternal transmission to progeny. Further investigation via imaging, biochemical analyses and ChIP assays revealed that POLDIP2 is a mitochondrial matrix protein capable of binding mtDNA. Moreover, we showed that CLPX, the key component of a major mitochondrial protease, interacts with POLDIP2 to co-regulate mtDNA elimination in Drosophila spermatids. This study sheds light on the mechanisms underlying mtDNA removal during spermatogenesis and underscores the pivotal role of this process in safeguarding maternal inheritance.

SUBMITTER: Hansong Ma

PROVIDER: S-SCDT-10_1038-S44318-025-00378-4 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Mitochondrial DNA (mtDNA) is a small, circular, double-stranded DNA inherited from the mother during fertilization. Evolutionary evidence supported by the endosymbiotic theory identifies mitochondria as an organelle that could have descended from prokaryotes. This may be the reason for the independent function and inheritance pattern shown by mtDNA. The unstable nature of mtDNA due to the lack of protective histones, and effective repair systems make it more vulnerable to mutations. The mtDNA and its mutations could be maternally inherited thereby predisposing the offspring to various cancers like breast and ovarian cancers among others. Although mitochondria are considered heteroplasmic wherein variations among the multiple mtDNA genomes are noticed, mothers can have mitochondrial populations that are homoplasmic for a given mitochondrial mutation. Homoplasmic mitochondrial mutations may be transmitted to all maternal offspring. However, due to the complex interplay between the mitochondrial and nuclear genomes, it is often difficult to predict disease outcomes, even with homoplasmic mitochondrial populations. Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency witnessed during the transmission of mtDNA from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be demonstrated. Despite initially thought to be limited to the germline, there is evidence that blockages exist in different cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. In this review, we comprehensively discuss the potential mechanisms through which mtDNA undergoes mutations and the maternal mode of transmission that contributes to the development of tumors, especially breast and ovarian cancers.

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POLDIP2 regulates mtDNA elimination during Drosophila spermatogenesis to ensure maternal inheritance

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