How Genes Cause Mitochondrial Diseases?

The Children's Hospital of Philadelphia experts have gained significant insights into how mitochondrial gene defects impair respiration, and other major life functions.

Marni J. Falk and her team carried out this research work using a simple model organism often studied in biology, known as Caenorhabditis elegans.

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Considering that mitochondria arose very early in evolution and play fundamental roles in multi-cellular organisms, learning the details of how mitochondria function in C. elegans provides useful clues to understanding their function in humans.

"Our ultimate goal is to translate the knowledge into targeted therapies, that is, effective ways to intervene. But first we need to understand the underlying disease mechanisms," said Falk, who directs the Mitochondrial-Genetics Disease Clinic at The Children's Hospital of Philadelphia.

During their study, Falk's team studied a biological pathway that occurs within mitochondria, called the respiratory chain.

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The researchers specifically focused on the largest component of that chain, complex I, which contains 45 subunits and is the most common culprit in human mitochondrial disease.

They studied the nuclear genes for 28 different complex I subunits that are very similar between humans and C. elegans, as well as two genes that help assemble the subunits into a functioning complex.

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Using a technique called RNA interference, they knocked out the function of each gene, and were able to determine how gene defects may contribute to mitochondrial diseases.

The study team found that one subset of genes impairs the ability of mitochondria to consume oxygen, called respiratory capacity, in C. elegans. Another group affects how the worms react to anaesthesia.

"Some children with mitochondrial complex I disease are hypersensitive to anaesthesia, so this new understanding may be important in guiding their clinical management," said Falk.

Her team continues to work to explore the many different consequences of mitochondrial respiratory chain dysfunction in animal models, and ways in which these consequences might themselves be treated.

This work helps to suggest specific genes that may be the cause of mitochondrial disease in individual patients, as well as clarify the biology of how specific genes may cause disease.

"Such work might one day benefit patients by pointing to specific drugs that alleviate secondary problems that arise when the respiratory chain cannot do its job," added Falk.

The study has been reported in the online journal PLoS One.

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