A research article published in the journal Science Advances describes a mechanism that helps explain how certain kinds of genetic disorders known as mitochondrial diseases are transmitted from mother to child. The study it reports could serve as the basis for novel strategies to ensure that future generations are not affected by such diseases. Existing treatments are palliative, aimed at improving quality of life for the patient or delaying progression of the disease. Show Mitochondria are organelles that generate most of the chemical energy needed by cells. Mitochondrial DNA (mtDNA) contains 16,569 nucleotides subject to mutation. Some of these mutations can lead to the development of mitochondrial diseases. Whereas nuclear DNA (the famous double helix, which encodes most of the genome) is inherited from both parents, mtDNA is inherited solely from the mother. At birth, a female infant’s ovaries already contain all the eggs she will ever have. During the reproductive cycles that begin at puberty, some of these immature eggs develop under the influence of hormones, leading to ovulation and potentially to fertilization. The study shows for the first time that mutant mtDNA builds up in the final stages of egg formation. The researchers conducted experiments in mice, reporting that the proportion of mutant molecules increased as the eggs matured, that these mutants can impair the functioning of mitochondria, and that they are responsible for the development of disease. At most 90% of the mtDNA was subject to mutation, the researchers discovered. The existence of an upper limit is important to an understanding of how mutant mtDNA is transmitted and can cause disease. 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. Now that we understand where and how it occurs, it’s possible to work out ways of avoiding it,” said Marcos Roberto Chiaratti, a professor in the Department of Genetics and Evolution at the Federal University of São Carlos (UFSCar) in the state of São Paulo, Brazil. Chiaratti and graduate student Carolina Habermann Macabelli are among the authors of the article. The study was supported by FAPESP via two projects (17/04372-0 and 16/07868-4). Chiaratti also received a Newton Advanced Fellowship from the UK’s Academy of Medical Sciences. He collaborates with the group led by Patrick Francis Chinnery, last author of the article. Chinnery is Professor of Neurology at the University of Cambridge, and Wellcome Trust Principal Research Fellow for its MRC Mitochondrial Biology Unit. “The most effective treatment entails identifying the mutation in 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,” Chiaratti said. The symptoms of mitochondrial disease vary according to the mutation, the number of damaged cells, and the tissue affected. The most common include weak muscles, loss of motor coordination, cognitive impairment, brain degeneration, and kidney or heart failure. Such hereditary metabolic diseases can appear at any age, but the earlier the mutation manifests itself, the more likely it is to lead to severe symptoms and even death. Diagnosis is difficult, typically requiring genetic and molecular testing, and statistics on prevalence are therefore deficient. According to estimates, diseases caused by mtDNA mutations affect at least one in every 5,000 people worldwide. However, the frequency of pathogenic mtDNA mutations is about one in 200. The mutation m.3243A>G, which causes MELAS syndrome (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes), occurs in some 80% of adults with pathogenic heteroplasmic mutations. ExperimentThe researchers studied genetically 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 present in humans. Analysis of 1,167 mother-pup pairs detected a strong tendency for females with low levels of m.5024C>T to transmit higher levels of the mutation to their offspring. In females with high levels of the mutation, however, the opposite tendency was detected, pointing to purifying selection against high levels of the mutation (over 90%). Analysis of mouse oocytes (immature eggs) at different stages of development showed rising levels of m.5024C>T over wild-type mtDNA. This suggests mutant mtDNA is preferentially replicated during oocyte maturation, regardless of the cellular cycle, as eggs do not undergo cell division until ovulation. The researchers tested several mathematical models, and the one that best explained the phenomenon pointed to a replicative advantage favoring mutant mtDNA and purifying selection that prevents the mutation from reaching high levels. They first measured heteroplasmy in 42 females and 1,167 descendants. Next, they 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. They found evidence that the results applied to mice bearing another pathogenic mutation (m.3875delC tRNA) and to humans, as indicated by analysis of 236 mother-child pairs. This pointed to positive selection when the mutation was transmitted 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% ceiling, above which the negative effect of mutations is too great and other mechanisms appear to act on the egg to prevent them from reaching 100%,” Chiaratti said. He plans to travel to the UK soon to conduct new experiments. A possible next step would be to proceed to the pharmacological treatment stage with the aim of combating levels of mtDNA mutation so as to prevent transmission of disease. “Once we understand how the buildup in mutations leading to mitochondrial disease occurs during the final stage of egg formation, we’re in a 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,” he said. Reference: Zhang H, Esposito M, Pezet MG, et al. Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission. Sci Adv. 7(50):eabi5657. doi: 10.1126/sciadv.abi5657 This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
Mitochondria are the “energy factory” of our body. Mitochondrial diseases are long-term, genetic, often inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly. One in 5,000 individuals has a genetic mitochondrial disease. Symptoms, diagnosis and treatment are discussed.
Energy-producing mitochondria in human cells. Mitochondria are the “energy factory” of our body. Several thousand mitochondria are in nearly every cell in the body. Their job is to process oxygen and convert substances from the foods we eat into energy. Mitochondria produce 90% of the energy our body needs to function. What are mitochondrial diseases?Mitochondrial diseases are chronic (long-term), genetic, often inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly. (Inherited means the disorder was passed on from parents to children.) Mitochondrial diseases can be present at birth, but can also occur at any age. Mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas. Mitochondrial dysfunction occurs when the mitochondria don't work as well as they should due to another disease or condition. Many conditions can lead to secondary mitochondrial dysfunction and affect other diseases, including: Individuals with secondary mitochondrial dysfunction don't have primary genetic mitochondrial disease and don't need to be concerned about the ongoing development or worsening of symptoms. How common are mitochondrial diseases?One in 5,000 individuals has a genetic mitochondrial disease. Each year, about 1,000 to 4,000 children in the United States are born with a mitochondrial disease. With the number and type of symptoms and organ systems involved, mitochondrial diseases are often mistaken for other, more common, diseases.
In most people, primary mitochondrial disease is a genetic condition that can be inherited (passed from parents to their children) in several ways. To understand inheritance types, it’s helpful to learn more about genes and DNA. Genes are substances that give us our traits, such as brown eyes or blue eyes. Genes contain DNA, which is the “blueprint” that gives each person their unique makeup. Under normal circumstances, a child inherits genes in pairs -- one gene from the mother and one from the father. A child with a mitochondrial disease does NOT receive a normal pair of genes from the parents. The gene has mutated – meaning it has become defective (changed). Learning the way a mitochondrial disease has been inherited helps predict the chance of passing on the disease(s) to future children. Inheritance types are:
What are the symptoms of mitochondrial diseases?Symptoms of mitochondrial diseases depend on which cells of the body are affected. Patients’ symptoms can range from mild to severe, involve one or more organs and can occur at any age. Even patients within the same family who have the same mitochondrial disease can have differences in symptoms, severity and age of onset (start of symptoms). Symptoms of mitochondrial diseases can include:
Because mitochondrial diseases affect so many different organs and tissues of the body, and patients have so many different symptoms, mitochondrial diseases can be difficult to diagnose. There is no single laboratory or diagnostic test that can confirm the diagnosis of a mitochondrial disease. This is why referral to a medical facility with physicians who specialize in these diseases is critical to making the diagnosis. Diagnosis starts with a series of examinations and tests that may include:
Other tests, depending on the patient’s symptoms and the areas of the body that are affected, might include:
More advanced testing could include biochemical testing, which looks for changes in body chemicals that are involved in energy making. Biopsies (samples) of skin and muscle tissue may also be performed.
There are no cures for mitochondrial diseases, but treatment can help reduce symptoms or slow the decline in health. Treatment varies from patient to patient and depends on the specific mitochondrial disease diagnosed and its severity. However, there's no way to predict a patient’s response to treatment or predict how the disease will affect that person in the long run. No two people will respond to the same treatment in the same way, even if they have the same disease. Treatments for mitochondrial disease may include:
Avoid situations that can make your medical condition worse. These include: exposure to cold and/or heat; starvation; lack of sleep; stressful situations; and use of alcohol, cigarettes and monosodium glutamate (MSG, a flavor enhancer commonly added to Chinese food, canned vegetables, soups, and processed meats).
The outlook for people who have mitochondrial diseases depends on how many organ systems and tissues are affected and the severity of disease. Some affected children and adults live near normal lives. Others might experience drastic changes in their health over a very short period of time. Some patients may have flare-ups of their disease, then return to a more stable state for years. Although there's no cure for mitochondrial diseases at the moment, research is ongoing. Parents with mitochondrial disease(s) who are considering having other children may want to consult a genetic counselor to discuss their concerns.
Last reviewed by a Cleveland Clinic medical professional on 05/31/2018. References
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