The devastation of mitochondrial disease is felt by millions of people worldwide, and approximately 1 in 4,300 people in the United States.
The mechanics of these diseases, which can lead to poor growth, muscle weakness, neurological problems and more, lie in the genes inside the mitochondria, which are the cell organelles that produce the cell’s energy. Mitochondrial genomes, which are inherited only from the mother, are distinct from the nuclear genomes that we tend to think of and which are inherited equally from mother and father.
In humans and other animals, mitochondrial genomes have extremely high mutation rates, and these mutations pass very easily from mother to child. Scientists are eager to learn more about the reasons for these high mutation rates and what could be done to stop them, so that mitochondrial disease can become a thing of the past.
Colorado State University biologists are funded by the National Institutes of Health to seek answers to these questions, but they’re not medical researchers — they’re plant biologists. It turns out that humans have a lot to learn from plants, from a genetic perspective, about how to keep our mitochondrial genomes free of disease-causing mutations.
How do plants undergo mitochondrial mutations?
Amanda Broz, a researcher in the lab of Dan Sloan, an associate professor in the Department of Biology, led a recent study published in Proceedings of the National Academy of Sciences which sheds new light on how plants, although rarely, undergo mutations in their mitochondrial genomes. Unlike humans, plants are able to quickly correct these mutations and, more importantly, not pass them on to their offspring.
In previous work, Sloan and members of his lab hypothesized that genes responsible for DNA replication, recombination, and repair in plant organelles like mitochondria and chloroplasts may be involved in maintaining these organelles healthy and without mutation. They looked at a gene called MutS homolog 1Where MSH1 to shorten it, found in plants but not in humans. By generating plants in the lab with mutations in this gene, they found evidence that this gene is essential for keeping mitochondrial mutation rates low in plants.
More detailed analysis followed, as they sought to understand how mutations in mitochondria and chloroplast genomes spread, both within the plant and across generations. What they found, and is detailed in their new paper, is that plants are very good at sorting through normal (good) and mutant (diseased) DNA. Once the sorting process is done, natural selection takes over: descendants who inherit diseased DNA are less likely to survive, so the mutation is not passed on to the offspring.
In contrast, diseased DNA in humans tends to get mixed up with the good and is passed down from generation to generation, as this sorting ability is much less efficient. In more technical terms, plants clear heteroplasmy – the presence of mutant and non-mutant DNA – from their cellular compartments much faster and more efficiently than their animal and human counterparts.
The researchers tracked the mitochondrial mutations they identified in a species called Arabidopsis in time and space using a sensitive technique called Digital Droplet PCR. This technique allowed them to analyze the amount of mutant mitochondrial DNA compared to normal mitochondrial DNA in these plants.
And, back to that special gene: Using the mutant plants they grew in the lab, CSU biologists discovered that working copies of MSH1 are what speed up the DNA sorting process in plant mitochondria. They think that MSH1 is responsible for first identifying mutations in mitochondrial DNA and repairing them. However, if a mutation persists for some reason, MSH1 can also work to quickly sort this mutation away from normal DNA.
“What’s really cool about our work is that it illustrates how nature has engineered multiple ways to deal with mutations in organelle genomes,” Broz said. “We know that mitochondrial mutations are one of the key drivers of aging and disease in humans. Knowing how plants and other organisms maintain such low mitochondrial mutation rates can help us better understand how this process goes awry in humans, and potentially how it can be remedied.”
Researchers still have a lot to learn from their mutant plants. They then create a mathematical model that attempts to understand what cellular forces are responsible for the different organelle DNA sorting rates they have observed in plants, and what role MSH1 plays in the process. This part of the project is led by collaborators from the University of Bergen in Norway. They are also trying to determine if MSH1 has the same impact on mitochondrial DNA sorting in other types of plants in addition Arabidopsis, like trees that have very different developmental patterns.