An evolutionary trait of humans and most animals is that they inherit mitochondrial DNA exclusively from the mother, even though the father's spermatozoa have mitochondria. If spermatozoa have mitochondria, why don't they transmit mitochondrial DNA?
An international team has answered this question in a study published in Nature Genetics, with the contribution of researchers from the Barcelona Biomedical Research Institute of the CSIC (IIBB). After several years of research, they have been able to demonstrate that spermatozoa do not have mitochondrial DNA and that, in addition, their mitochondria lack a transcription factor A mitochondrial (TFAM), which is essential for human mitochondrial DNA to replicate.
Without mitochondrial DNA
"In many species, including humans, sperm mitochondria are introduced into the egg during fertilisation, so one of the existing hypotheses was that the mitochondrial DNA did reach the oocyte but was eliminated during the fertilisation process," explains Ramón Trullás, researcher at the Neurobiology Unit of the IIBB-CSIC-IDIBAPS and the Centre for Biomedical Research in the Neurodegenerative Diseases Network (CIBERNED). Ramón Trullás is one of the authors of the study, carried out with his team, Anna Calderon, Margalida Puigròs and Petar Podlesniy, together with the team of Shoukhrat Mitalipov (Oregon Health & Science University, USA) and coordinated by Dmitry Temiakov and his team William Lee, Angélica Zamudio-Ochoa and Gina Buchel (Thomas Jefferson University, USA).
To find out whether spermatozoa have mitochondrial DNA, the IIBB-CSIC researchers have developed a digital PCR technique, which is more accurate than conventional PCR and allows the absolute number of DNA in different cell types to be quantified in the same sample. The analyses were carried out on samples from clinics in Oregon (USA).
The results show that spermatozoa do not have a single complete molecule of mitochondrial DNA, and that the residual mitochondrial DNA found probably does not even belong to them. "Each sperm cell contains between 50 and 70 mitochondria, corresponding to less than 0.01 molecules of mitochondrial DNA per mitochondrion. Although extremely low, this number likely accounts for the background mitochondrial DNA detected in a few contaminating cells (namely leukocytes)," the authors explain in the paper.
The researchers discovered that the absence of DNA in sperm mitochondria is due to the re-localization of the transcription factor TFAM, an essential molecule that penetrates the mitochondria to replicate mitochondrial DNA. During spermatogenesis, the spermatozoon modifies the mitochondrial localization signal of TFAM and does not allow it to enter the mitochondria but directs it to the sperm nucleus, therefore preventing mitochondrial DNA replication.
"Our work shows that the modification of TFAM during spermatogenesis results in the elimination of mitochondrial DNA and explains its maternal inheritance. A fascinating process, a product of evolution, that prevents the inheritance of paternal DNA," adds Ramon Trullas.
This discovery of TFAM re-localization has important implications for the fields of human fertility and germ cell therapy, as it could explain some cases of oligospermia and oligoasthenospermia, disorders that affect sperm count and sperm motility, causing male infertility. In fact, elevated levels of mitochondrial DNA have been found in the sperm of infertile men with severe oligoasthenospermia, the researchers say.
Reference article:
Molecular basis for maternal inheritance of human mitochondrial DNA, William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchen, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov & Dmitry Temiakov. Nature Genetics, doi: https://doi.org/10.1038/s41588-023-01505-9
