Fewer Mutations in Tumor Mitochondria

Contrary to existing dogma, colon cancer cell mitochondria carry fewer mutations than mitochondria of normal body cells.

By | June 7, 2012

image: Fewer Mutations in Tumor Mitochondria Mitochondria light up a cell. THE CELL

Mitochondria light up a cell.THE CELL

Mitochondrial DNA (mtDNA) in colon cancer cells undergoes less frequent mutation than healthy body cell mtDNA, according to a study published in PLoS Genetics this week (June 7). The finding flies in the face of the popular belief that tumor cell DNA is more highly mutated than the genetic code of normal cells, as has been established for nuclear DNA, and suggests a decoupling of nuclear and mitochondrial processes as colon cancer advances.

“The result impacts our understanding of the underlying mechanisms that take place during carcinogenesis,” said Lars Eide, a medical biochemistry professor at the Institute of Clinical Medicine in Oslo who works on mtDNA stability but was not involved in the study, by e-mail. “The increased fidelity of mtDNA during the carcinogenic process indicates that mtDNA mutations are not responsible for tumor formation.”

Cancer geneticist Jason Bielas of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues decided to comb mutations in the mtDNA of colon cancer cells for alternative biomarkers of cancer development. Cells contain thousands of times more mtDNA than nuclear DNA, so less material would be required to assess the progress of a cancer.

While there is currently no method that can detect the rate of change, Bielas developed a sensitive method of mutation frequency detection, called the Random Mutation Capture Assay, based on the ability of a mutation to inhibit a restriction enzyme's active site. This method digests all wild-type DNA, leaving behind only mutations and has a higher resolution than traditional methods, making it sensitive to mtDNA mutation frequencies approximately 100-fold lower than those detected by PCR, for example.

What they found surprised them. Rather than finding higher mutation rates compared with healthy tissue, they found that the mtDNA of the cancer cells carried fewer mutations.

“It almost seems like it’s an oasis,” said Bielas. “Most of the cancer cell looks like a bomb exploded inside, and yet you have this preserved genome.”

Bielas says the result suggested two possible mechanisms for new cancer therapies. Firstly, if healthy mitochondria are associated with growing tumors, then introducing more mutations to mitochondria may slow a tumor's progress. Bielas and his team are now testing the hypothesis that decreasing mutations in the mitochondria will make cancer cells more resistant to chemotherapeutic agents. If this is the case, they will then work on targeting the mitochondria to make them more sensitive.

“We definitely know there’s a lot of mutagens and chemotherapeutic agents that specifically target mitochondria,” said Bielas. “But this may not be the best way to approach this with minimal side effects.”

One reason mitochondria in cancers suffer fewer mutations may be that they are no longer providing the cells’ oxygen, reducing their oxidative stress. Mitochondrial activity has been associated with aging and cell death, and the theory here is that cancer cells shift to glycolysis, a non-oxidative form of metabolism, during their growth. This protects the cancer cell from the reactive oxygen species produced during oxidative metabolism carried out in the mitochondria, and may help them live longer. Reprogramming cancer cells to start using oxygen again may provide a second mechanism of cell destruction, likely with fewer side effects than targeting mitochondria. Bielas says they are investigating both methods, but that reprogramming cells is “more difficult.”

In addition to possible new cancer treatments, Bielas is optimistic that his Random Mutation Capture Assay may serve as a detection aid for identifying tumor-associated mutations that have made it into circulation.

N. Ericson et al., "Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer," PLoS Genetics, doi:10.1371/journal.pgen.1002689, 2012

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Avatar of: S_Pelech_Kinexus

S_Pelech_Kinexus

Posts: 3

June 8, 2012

Another reason why mutations in mitochondria in tumour cells might be less evident is because there can be up to thousands of individual mitochondria within each cell, each of which have their own similar but not identical genome. Detection of specific mutations that are generated randomly in the mitochondrial DNA would be much harder to detect against this background. Presumably defective mitochondria can be replaced by their less affected sisters in the same tumour cell to still support its survival.

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