Gene coupled to male infertility

STONY BROOK U. (US) — A new role for mitochondria may hold clues to some causes of male infertility and in turn could have potential in the future for use in a male contraceptive.

Mitochondria help regulate different cell biological processes involving communication between the mitochondria and the rest of the cell by way of signaling pathways on the surface that mediate interactions with cytoplasmic proteins. Some of the pathways involve lipids.

“Our experimentation uncovered a new role for mitochondria in a specialized form of RNA-processing that appears to take place at the interface between the mitochondrial surface and adjacent granules of RNA and RNA-associated proteins,” says Michael Frohman, professor of pharmacologicial sciences at Stony Brook University.

“More specifically, we linked a signaling enzyme on the mitochondrial surface, called MitoPLD, to the production of piRNAs, which are produced from RNA copies early in spermatogenesis during meiosis.”

PiRNAs are known for suppressing cellular transcription (copying of RNA) and mobilization of genetic elements known as transposons, which make up almost half of the human genome. Many types of piRNAs also target non-transposon genes.

But without piRNAs, transposons replicate, leading to widespread DNA damage that subsequently leads to the death of differentiating sperm cells.

The study is reported in the journal Developmental Cell.

Furthering the research, the team genetically engineered mice to lack the MitoPLD gene and found the mice to be normal, except that the males were infertile. No effect has been seen on female fertility.

“The long-term potential significance of our laboratory findings is the possibility that some cases of male infertility may be caused by inherited mutations in MitoPLD, the signaling enzyme, especially since at least one inactivating mutation is found in the database of sequenced human DNA,” Frohman says.

“Conversely, pharmacological inhibitors of MitoPLD could have potential utility as male contraceptives.”

In their study, titled “piRNA-Associated Germline Nuage Formation and Spermatogenesis Require MitoPLD Profusogenic Mitochondrial-Surface Lipid Signaling,” the authors point out that

Despite the findings, the piRNA generation pathway is complex and the mechanism underlying MitoPLD effects on mitochondrial morphology and fusion are unknown, Frohman says, but the biological significance of the work has pharmacological potential.

“Because inhibitors have been developed for other members of the same enzyme family, MitoPLD is likely a feasible target.”

Researchers from the University of Kentucky, Lexington; and the Chonnam National University Medical School in Korea contributed to the study.

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