Mitochondrial Diseases: the Cracked Bottleneck of Inheritance

Author:  Ramlagan Nadia

Date:  February 2008

Patrick Chinnery at Newcastle University and a team of international scientists have opened a new door into predicting a child's risk of inheriting a mitochondrial disease that can result in stroke, diabetes, heart failure, cognitive impairment and dementia. They've discovered how diseases caused by mutant mitochondrial DNA (mutant mtDNA) pass down from mother to child, and why the severity of mtDNA diseases differs widely between siblings and amongst individuals.

Research published in Nature Genetics showed that a mother's mtDNA is divided and replicated into different cells, and then segregated between the new cells of offspring. This process only allows for a small number of mtDNA molecules to be given to the next generation, thereby suppressing the amount of mutant mtDNA passed down, like the structure of many beverage bottles where the neck of the bottle regulates the amount of liquid that is poured at a time. While the overall quantity of mtDNA inherited might be small, some eggs may still end up with a significant amount.

"A mother can pass on a small proportion of mutant mtDNA, or a very high proportion, and this can make the difference between a child being born without disease and another having a very severe form of the disease," said Chinnery.

Using a principle of population genetics called random segregation, Professor Chinnery simulated the process of mtDNA segregation in mice. His results proved this bottleneck does in fact exist and causes the dramatic reduction in the number of mtDNA molecules in the cells that eventually form the eggs. This leads to the wide variation in the severity of disease. Depending on which egg is fertilized, a high proportion of abnormal mitochondria may be passed on to the child. In this case, the child will be more severely affected than the mother.

Mitochondria are the "powerhouses" of cells. They are structures within cells that provide energy by converting the food we eat into the form that cells use, ATP (adenosine triphosphate). Mitochondria are unique because they have a small amount of their own DNA. The current accepted theory suggests that millions of years ago mitochondria were independently functioning bacteria. These bacteria formed symbiotic relationships with larger cells, where both organisms conferred a benefit to the other. Eventually, mitochondria became completely dependent on the larger cells and remained within them, transferring all except a small portion (what is now called mitochondrial DNA) over to the larger cells.

Up until now, scientists did not understand the mechanism that causes mtDNA diseases, which are thought to affect about one person in 5,000, to develop so differently among siblings, from mild to extremely severe. As a result, even when the precise proportion of abnormal mtDNA carried by the mother is known, scientists have been unable to predict whether and how a child will be affected. Nevertheless, Dr. Chinnery offers an optimistic perspective on the development of understanding mitochondrial disease

"Now that we understand how different levels of abnormal mtDNA are inherited, we may soon be able to predict a child's risk of disease and the level of severity." concluded Chinnery.

Written by Nadia Ramlagan

Reviewed by Brandy Sullivan

Published by Pooja Ghatalia.