Is there a correlation between mitochondrial DNA and leukemia?

Mitochondria, the energy source of cells, also contain DNA. This is called mtDNA. Human mtDNA is considered the smallest chromosome and consists of 37 genes primarily responsible for energy production and approximately 16,600 base pairs.

A new study has shown that mutations occurring in this mtDNA are correlated with the development of leukemia. This is what Medical Express, a medical media outlet, reported on the 2nd (local time) based on a paper by researchers at St. Jude Children’s Research Hospital in the U.S. published in Science Advances.

Mitochondria are essential for cellular energy production and therefore play an important role in promoting cancer growth. Mutations occur in mtDNA in the same way as DNA found in the nucleus. However, it was unclear how mtDNA affected cancer cells.

Researchers led by Dr. Mondara Kundu, a cell and molecular biologist at St. Jude Children’s Research Hospital, studied different levels of mutated mtDNA to determine its effect on leukemia cells. As a result, it was found that cancer growth was blocked in cells with mutations in all mtDNAs, while cancer growth significantly increased in cells with mutations in about half of the mtDNAs.

The researchers also discovered that by amplifying an enzyme essential for energy production, cancer growth could be resumed in leukemia cells that had mutations in all mtDNAs. These findings suggest that there is an unknown link between mitochondrial DNA and metabolic functions in cancer cells.

Dr. Kundu pointed out, “Research results are mixed regarding the impact of mitochondrial DNA mutations on cancer.” Some papers claim that this mutation promotes tumor formation, while others point out that it has no effect.

Because of the large number of mitochondria in each cell, introducing individual mutations into mtDNA is difficult. Instead, the researchers used a leukemia mouse model with a defect in a genetic correction system called Polg to gradually generate mtDNA mutations.

By interfering with Polg’s proofreading function in one (heterozygous) or both (homozygous) parental lines, the researchers were able to look at the burden on tumor growth based on the number of mitochondria with mtDNA mutations. As a result, they found that heterozygous mice (mice with an appropriate number of mutant mitochondria) had amplified leukemia growth. On the other hand, homozygous mice with a higher number of mutations had the opposite effect, blocking tumor growth.

“Until now, researchers have focused on an ‘all or nothing’ approach, thinking that many mutations impair tumor function,” Kundu said. “However, our findings suggest that in the case of leukemia, moderate mitochondrial mutations may promote leukemogenesis,” he explained.

This effect may be related to the ability of leukemia cells to reprogram their metabolism (plasticity) to thrive in the harsh tumor microenvironment. “The amount of metabolic stress caused by mtDNA mutations increases cellular plasticity,” explained Dr. Kundu.

Accordingly, exposure to slight metabolic stress in heterozygous mice can easily lead to transformation by different oncogenes. On the other hand, in homozygous mice, it basically stops working. The explanation is that these differences can have a significant impact on metabolism.

The research team investigated the mechanism by examining ‘pyruvate dehydrogenase’ (PDH), which regulates metabolic plasticity of cells. PDH connects the two stages of cellular respiration, glycolysis and the citric acid cycle.

Glycolysis is when glucose is broken down into pyruvate, creating two ATP (adenosine triphosphate) molecules. The citric acid cycle causes pyruric acid to enter the mitochondria and produce more ATP molecules. PDH helps regulate the metabolic plasticity of cells by linking them.

The researchers discovered that the plasticity of leukemia cells could be restored in homozygous (highly mutated) mice by blocking the ‘off switch’ of the pyruvate dehydrogenase kinase. This suggests that promoting the operation of the citric acid cycle, which is blocked in the homozygous model, restores the growth of the corresponding cells.

Collectively, our findings provide clear evidence that low-to-moderate mtDNA mutations can aid leukemogenesis and that complete disruption of mitochondrial function can have the opposite effect, essentially halting tumor growth.

The paper can be found at the following link: