Xiujie Li-Harms, PhD, (pictured) director of laboratory operations in the lab of Mondira Kundu, MD, PhD, St. Jude Department of Cell & Molecular Biology, and first author on research published in Science Advances demonstrating the impact of mitochondrial DNA mutational burden on leukemogenesis, revealing a mutational ‘sweet spot’, where leukemia development was amplified.
Mitochondria are vital to energy production in cells and so play a key role in fueling cancer growth. However, how mitochondrial DNA (mtDNA) contributes to cancer has been unclear. Scientists at St. Jude Children’s Research Hospital studied varying levels of mutated mtDNA to see their effect on leukemia cells. They found that while cancer growth was blocked in cells in which all mitochondria contained mutated mtDNA, it was notably increased in cells with moderate amounts of mutated mtDNA. By amplifying an enzyme vital to energy production, the researchers we also able to restart cancer growth in leukemia cells with fully mutated mtDNA. Collectively, these findings highlight an unexplored connection between mitochondrial DNA and cancer cells’ metabolic function. The findings were published today in Science Advances.
mtDNA is found exclusively within mitochondria and contains just 37 genes, which are largely responsible for energy production. Mutations occur to this DNA in the same way as DNA found in the nucleus, but studying the effect these mutations have on cancer is much more challenging. Recent advances have allowed Mondira Kundu, MD, PhD, St. Jude Department of Cell & Molecular Biology, to begin to address this knowledge gap.
“The role of mitochondrial DNA mutations in cancer is controversial,” said Kundu. “Some papers suggest they are pro-tumorigenic, and others say they have no impact. It’s essentially been unknown.”
Leukemia thrives in mtDNA mutation ‘sweet spot’
Introducing individual mutations to mtDNA is challenging due to the large number of mitochondria within each cell. Instead, the researchers used a leukemia mouse model with a defective genetic proofreading system called Polg, which gradually accrues mtDNA mutations. By disrupting Polg’s proofreading function in either one (heterozygous) or both (homozygous) parental lines, the researchers could look at the burden that mtDNA mutations place on tumor growth based on the number of mitochondria with mutated mtDNA.
The researchers found that heterozygous mice (those with a moderate number of mutated mitochondria) seemed to amplify leukemia growth. Homozygous mice with a high number of mutations had the opposite effect, blocking tumor growth.
“Until now, researchers have been focusing on an all-or-nothing approach, thinking that a lot of mutation impairs tumor function,” Kundu explained, “but in terms of leukemia, our findings suggest that an intermediate level of mitochondrial mutations might promote leukemogenesis.”
This effect may be related to the ability of leukemia cells to reprogram their metabolism to thrive in a harsh tumor microenvironment (their plasticity). “The amount of metabolic stress [from mtDNA mutation] increases the plasticity of the cells,” she explained. “So, exposure to a little bit of metabolic stress in the heterozygous mice may increase the susceptibility to transformation by different oncogenes, whereas in the homozygous mice, they are basically shutting down. The impact on metabolism was so severe that it could not be overcome.”
Metabolic plasticity connects mtDNA and tumor growth
To explore the mechanisms behind this, the researchers looked at an enzyme called pyruvate dehydrogenase. This enzyme links the two stages of cellular respiration: glycolysis and the citric acid cycle. In doing so, pyruvate dehydrogenase helps regulate the metabolic plasticity of cells. The researchers found that by blocking the kinase “off switch” of pyruvate dehydrogenase, they could restore leukemia cells’ plasticity in the homozygous (high mutation) mice. These results suggest that the citric acid cycle shuts down in the homozygous models, so promoting it restores the growth of those cells.
Collectively, the findings provide clear evidence that low to medium levels of mtDNA mutations can contribute to leukemogenesis and that complete disruption of mitochondrial function can have the opposite effect, essentially halting tumor growth.
Authors and funding
The study’s first author is Xiujie Li-Harms, St. Jude. The study’s other authors are Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin Kaminski, Hailey Ross, Christopher Wright, Amber Ward, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoff Neale, Peter Vogel, Stanley Pounds, John Schuetz and Min Ni, St. Jude.
The study was supported by grants from the National Institutes of Health (R01MH115058, R01GM132231 and R01CA194206) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.