An investigation that is published in the magazine ‘Nature Genetics‘ provides information on the fundamental scientific principle that mitochondrial DNA (the distinctive genetic code embedded in the organelle that serves as the powerhouse of each cell in the body) is transmitted exclusively by the mother. The information is especially relevant for mitochondrial replacement therapies, gene therapies that could prevent mitochondrial diseases.
It has long been assumed that mitochondrial DNA, or mtDNA, comes exclusively from human eggs, meaning that only the mother provides the genetic code carried by thousands of mitochondria necessary for energy production in each cell of the body.
Until now, it was thought that paternal mtDNA was removed shortly after a sperm fused with an oocyte, or developing egg, during fertilization, possibly through a search-and-destroy response similar to the immune system.
However, the study has found that while mature sperm contain a small number of mitochondria, they lack intact mtDNA.
“We have discovered that each sperm has about 100 mitochondria as organelles when it fertilizes an egg, but they do not contain mtDNA,” explains co-author Shoukhrat Mitalipov, director of the Center for Gene Therapy and Embryonic Cells at OHSU.
The researchers reveal that sperm not only lack intact mtDNA, but also lack a protein essential for mtDNA maintenance, known as mitochondrial transcription factor A or TFAM.
Although they are not sure why sperm are not allowed to contribute mtDNA, Mitalipov theorizes that it may be related to the fact that a sperm uses a lot of mitochondrial energy in its biological drive to fertilize an egg.
Therefore, he explains, it would accumulate mutations in the mtDNA. In contrast, developing eggs known as oocytes draw energy primarily from surrounding cells, not their own mitochondria, so they maintain relatively pristine mtDNA.
«Eggs pass on really good mtDNA, at least in part, because they don’t use mitochondria as an energy source», clarifies Mitalipov.
The sperm’s approximately 100 organelles are inundated by hundreds of thousands of mitochondria embedded in each egg, each carrying the 37 genes of mitochondrial DNA. The contribution of maternal mtDNA alone is thought to confer an evolutionary advantage by limiting the risk of accumulations of disease-causing mtDNA mutations in offspring.
Mitochondria control respiration and energy production within every cell in the body, so mutations in mtDNA can cause a variety of potentially fatal disorders that affect organs with high energy demands, such as the heart, muscles and brain.
To help mothers prevent the transmission of known mtDNA disorders to their children, Mitalipov pioneered a method called mitochondrial replacement therapy to replace mutant mtDNA through in vitro fertilization using healthy mtDNA from donor eggs.
The US Congress has prevented the Food and Drug Administration (FDA) oversee clinical trials using this procedure in the US, so clinical trials are being conducted abroad, including clinical trials in the UK to prevent disease and in Greece to treat infertility.
The researchers write that the new discovery has important implications for human fertility and germ cell therapy.
«Understanding the role of TFAM during sperm maturation and its function during fertilization may be key to our ability to treat certain infertility disorders and increase the efficiency of assisted reproductive technologies.», says researcher Dmitry Temiakov, from the Thomas Jefferson University in Philadelphia.
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