Electron micrograph of a mitochondrion. New research suggests that mutant mitochondria might be responsible for male infertility.
SYDNEY: Male mice with mutant mitochondria - the energy-producing component of cells - have lower sperm counts, sluggish sperm and produce fewer offspring, pointing to a new culprit in human infertility, a team of Japanese researchers say.
Their findings, published today in the U.S. journal Proceedings of the National Academy of Sciences, suggest that in human males suffering from infertility – some eight per cent of couples – it might be their mitochondria that's to blame.
“On the basis of these findings, we would like to suggest that some cases of human male infertility ... might result from mitochondrial respiratory dysfunction”, said chief investigator Kazuto Nakada of the University of Tsukuba in Japan.
Mitochondria supply every cell’s energy needs, with most cells in the human body containing between 1,000 and 10,000 mitochondria. Each mitochondrion has its own genome, separate from the majority of our DNA which is located in the nucleus.
Researchers have previously identified mutations in mitochondrial DNA in patients with fertility problems, however the exact link between the two has been unclear until now.
In order to explore the importance of mitochondrial function in fertility, Nakada and colleagues created “mito mice”: male mice with different levels of mutant mitochondria which was missing a large stretch of DNA. These mice were incapable of expressing several key proteins involved in energy production.
Nakada and colleagues were able to introduce varying amounts of the mutant mitochondria into mice: some contained less than 10 per cent mutant mitochondria, while others had over 80 per cent. Apart from the introduced mitochondria, each mouse had the same genetic background, which allowed the researchers to attribute any pathological effects to the mutant mitochondria present.
Mice with over 70 per cent mutant mitochondria had difficulty undergoing meiosis, which is the basis of sperm production, and the sperm they did produce had increased morphological abnormalities and decreased swimming ability. The researchers conclude that “mitochondrial respiration activity is essential for mammalian spermatogenesis [sperm production]”.
Interestingly, there was no difference between mice with no mutant mitochondria and those with up to 70 per cent, in terms of healthy sperm production or number of offspring fathered. On the other hand, mice with over 80 per cent mutant mitochondria were not only infertile, but also suffered from a range of other disorders, including low body weight, renal failure and deafness.
According to the researchers, male mice are able to tolerate malfunctioning mitochondria up to a threshold, above which serious problems develop. Nakada believes this threshold is more likely to be reached in individuals with a family history of mitochondrial mutations, rather than in those who acquire the damage during their lifetime.
In contrast to males, female mice with mutant mitochondria had unimpaired fertility. This could relate to the way that mitochondria are inherited. According to Nakada, “the mammalian female might have evolved the strategy of selecting only the healthy eggs - those carrying relatively lower amounts of mutated mitochondrial DNA - because mitochondrial DNA is inherited maternally.”
Nakada believes that this research could help generate new drug leads. “Sperm samples from the mice with mitochondria-related male infertility could be utilised for screening drugs designed to restore mitochondrial respiratory dysfunction.”
Apart from treating male infertility, he also believes such drugs could be used in the treatment of other conditions, such as Parkinsons disease, diabetes, and ageing.
