Sweet Spot of Mitochondrial Mutations Fuels Cancer Growth
Moderate mitochondrial DNA mutations enhance leukemia growth, while high mutation levels halt tumor development.
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.”
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.”
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.
Mitochondrial DNA mutations, oxidative phosphorylation, mitochondrial genome, heteroplasmy, mtDNA copy number, mitochondrial dysfunction, mitochondrial diseases, somatic mutations, inherited mutations, oxidative stress, ATP production, bioenergetics, mitochondrial biogenesis, electron transport chain, mitochondrial ROS, mitochondrial repair mechanisms, mitochondrial dynamics, mitochondrial fusion, mitochondrial fission, mitochondrial quality control.
#Mitochondria #GeneticMutations #MitochondrialDNA #MitoDiseases #OxidativeStress #EnergyProduction #MitochondrialHealth #Bioenergetics #MitochondrialResearch #mtDNA #CellMetabolism #Genomics #MitochondrialFunction #MitoBiology #DNARepair #MitochondrialFusion #MitochondrialFission #OxPhos #ReactiveOxygenSpecies #HealthandGenetics
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.
Mitochondrial DNA mutations, oxidative phosphorylation, mitochondrial genome, heteroplasmy, mtDNA copy number, mitochondrial dysfunction, mitochondrial diseases, somatic mutations, inherited mutations, oxidative stress, ATP production, bioenergetics, mitochondrial biogenesis, electron transport chain, mitochondrial ROS, mitochondrial repair mechanisms, mitochondrial dynamics, mitochondrial fusion, mitochondrial fission, mitochondrial quality control.
#Mitochondria #GeneticMutations #MitochondrialDNA #MitoDiseases #OxidativeStress #EnergyProduction #MitochondrialHealth #Bioenergetics #MitochondrialResearch #mtDNA #CellMetabolism #Genomics #MitochondrialFunction #MitoBiology #DNARepair #MitochondrialFusion #MitochondrialFission #OxPhos #ReactiveOxygenSpecies #HealthandGenetics
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