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In silico modeling helps predict severity of mitochondrial disease

A team of researchers in Australia, the United Kingdom and the United States has revealed how mitochondrial diseases are passed from the mother to the next generation in a mouse model system. The study, which was published on-line in Nature Genetics*, shows for the first time how mitochondrial diseases that cause muscle weakness, diabetes, stroke, heart failure and epilepsy are passed from mother to offspring.

Mitochondria are the engines present in each cell that produce adenosine triphosphate (ATP), the key energy currency that drives metabolism. Mitochondria also have their own DNA (mitochondrial or mtDNA) that encodes a small but essential number of proteins required for energy production in cells. Mitochondria, and the mtDNA that they contain, are inherited solely from the mother, as the paternal mtDNA present in the sperm are destroyed after the egg is fertilized. In almost all diseases caused by mutant mtDNA, the patients cells will contain a mixture of mutant and normal mtDNA. The proportion of mutant mtDNA in most cases determines the severity of the disease.

The inheritance of these diseases does not follow the rules of Mendelian genetics. Instead, there are large random shifts at the mtDNA mutation level between mother and offspring. This study explains how these large random shifts occur within the first three weeks of embryo formation, through the combined use of computational modeling and a mouse model system.

Dr. David Samuels, assistant professor at the Virginia Bioinformatics Institute (VBI), commented: The computational model used in this investigation simulates the biological process directly and allows scientists to examine the early stages of embryo formation and development. Clinicians can therefore take a close look at the replication of mitochondrial DNA and the dynamics of cell division in mouse embryos before and after implantation in the uterus. He added: Computational modeling and cutting-edge lab work were both essential for this study. The experiments gave us new information that we had to have to build the simulation, and the simulation was used as a tool to analyze the data from the experiment.

Dr. Patrick Chinnery, Wellcome Senior Fellow in Clinical Science and professor of neurogenetics at the University of Newcastle in the United Kingdom, remarked: Mitochondrial disease can have devastating effects on a family, and the chance of having affected children is a cause of major stress. By defining the main biological mechanism, we hope in the long term to develop counseling guidelines that will help patients and their families make more informed decisions.

The computational model reveals how mtDNA is divided into different embryonic cells before and after implantation and how the replicating mtDNA molecules are subsequently separated between the dividing germ cells that make up the embryo. The model accounts for the marked reduction in the number of mtDNA molecules that are transmitted from mother to offspring, the so-called mitochondrial genetic bottleneck. It is thought that this genetic bottleneck has evolved over time to remove deleterious mitochondrial mutations from the population. These mutations are either lost during transmission or, if transferred, give rise to offspring with a low chance of survival.

Although the current study investigates the transmission of mitochondrial DNA in mice, the computational model is also applicable to human data. Mitochondrial diseases are thought to affect as many as one person in 5000. The research offers the hope that clinicians will be able to predict a childs risk of developing maternally inherited mitochondrial diseases that cause muscle weakness, diabetes, stroke, heart failure and epilepsy.


Contact: Barry Whyte
Virginia Tech

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