A research article in the journal Science Advances outlines a technique that helps explain how certain kinds of mitochondrial diseases are transmitted from mother to child. It suggests that future generations may be non-infected with such diseases. Existing treatments are palliative, aimed at improving the patient''s quality of life or causing the disease to develop.
Mitochondria are organelles that consume the majority of the chemical energy they need from cells. Its mitochondrial DNA (mtDNA) contains 16,569 nucleotides that have been altered. Some of these modifications might lead to the development of mitochondrial illnesses.
mtDNA is inherited only from the mother, as is nuclear DNA (the famous double helix, which encodes the majority of the genome).
During pregnancy, a female infant ovaries already has all of the eggs she will ever have. During pregnancy, some of these immature eggs develop under the influence of hormones, leading to ovulation and potentially fertilization.
For the first time, mutant mtDNA builds up in the final stages of egg formation. The researchers conducted experiments in mice, indicating that the proportion of mutant molecules increased as the eggs matured, that these mutants can impair mitochondrial functioning, and that they are responsible for the development of disease.
The researchers discovered that at least 90% of the mtDNA was subjected to mutation. It is very important to understand how mutant mtDNA is transmitted and can cause cancer.
When mutant and wild-type mtDNA coexist in a cell (heteroplasmy), the effects of mutant mtDNA may be masked, facilitating transmission to offspring. Until now, no one knew if this buildup occurred, but our study proved it does. It is possible to work out ways of avoiding it, according to Marcos Roberto Chiaratti, a professor in the Department of Genetics and Evolution at the Federal University of Sao Paulo in Brazil.
Carolina Habermann Macabelliare, a graduate student, has been chosen to the top of the article. FAPESP has aided the study through two projects (17/04372-0 and 16/07868-4).
Chiaratti has also received a Newton Advanced Fellowship from the UKs Academy of Medical Sciences. He works with the group led by Patrick Francis Chinnery, the last author of the article. Chinnery is a Professor of Neurology at the University of Cambridge and a Wellcome Trust Principal Research Fellow for its MRC Mitochondrial Biology Unit.
The most effective treatment involves identifying the mother in order to prevent inheritance by the children. This is the context for our research, which aims to verify which mutations are transmitted and analyze the mechanism involved. The study of mitochondrial disease in Brazil is still very incipient.
The symptoms of mitochondrial disease vary according to the mutation, the number of damaged cells, and the tissue affected. The most common are weak muscles, cognitive impairment, brain degeneration, and kidney or heart failure.
These hereditary metabolic diseases may occur at any time, but the earlier the mutation manifests itself, the greater likely it to cause severe symptoms and even death. Diagnosis is often complicated, requiring genetic and molecular testing, and prevalence statistics are deficiency.
Diseases caused by mtDNA mutations affect at least one in every 5,000 people around the globe. However, the frequency of pathogenic mtDNA mutations is one in 200. The mutation m.3243A>G, which causes MELAS syndrome (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes), occurs in about 80 percent of adults with pathogenic heteroplasmic mutations.
The researchers studied gynically modified mice with two types of mitochondrial genome: the wild type, which does not cause disease, and the pathogenic mutation m.5024C>T, similar to m.5650G>A, a pathogenic mutation found in humans.
The results from a survey of 1,167 mothers-pup pairs indicated that females with low levels of m.5024C>T were likely to transmit higher levels of the mutation to their offspring. Despite the opposite tendency, the selection was purified against high levels of the mutation (over 90%).
High levels of m.5024C>T on wild-type mtDNA have been demonstrated during oocyte maturation, regardless of the cellular cycle, as eggs do not undergo cell division until ovulation.
The researchers used several mathematical models to demonstrate a replicative advantage in favor of mutant mtDNA and purifying selection, which prevents the mutation from reaching high levels.
In addition to measuring heteroplasmy in 42 females and 1,167 descendants, they then measured levels of mutant mtDNA in eggs at different stages of development and compared them with levels of mutation in different organs at different ages.
Results from a research of 236 mothers-child pairs demonstrated that the mutation was withdrawn from mothers with low heteroplasmy levels and purifying selection against high heteroplasmy levels (over 90%). They concluded that positive selection resulted from a preference for replication of the mutant over the wild-type molecule.
This preferential replication enabled the level of mutation to reach the 90% threshold, above which the negative effect of mutations is too big and other measures appear to act on the egg to prevent them from reaching 100%.
He intends to conduct future experiments in the United Kingdom soon. A potential next step would be to proceed to the pharmacological treatment phase in order to prevent disease transmission. Once we understand how mutations that result in mitochondrial disease occurred during the final stage of egg formation, we were in the position to produce eggs in vitro and manipulate them, pharmacologically as well as genetically, in order to reduce mutation levels, lowering the probability that a child will develop the disease.