Skip to main content

Mitochondrial Mutations

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.”

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

Comments

Popular posts from this blog

Fruitful innovation

Fruitful innovation: Transforming watermelon genetics with advanced base editors The development of new adenine base editors (ABE) and adenine-to-thymine/ guanine base editors (AKBE) is transforming watermelon genetic engineering. These innovative tools enable precise A:T-to-G and A:T-to-T base substitutions, allowing for targeted genetic modifications. The research highlights the efficiency of these editors in generating specific mutations, such as a flowerless phenotype in ClFT (Y84H) mutant plants. This advancement not only enhances the understanding of gene function but also significantly improves molecular breeding, paving the way for more efficient watermelon crop improvement. Traditional breeding methods for watermelon often face challenges in achieving desired genetic traits efficiently and accurately. While CRISPR/Cas9 has provided a powerful tool for genome editing, its precision and scope are sometimes limited. These limitations highlight the need for more advanced gene-e...

Genetic factors with clinical trial stoppage

Genetic factors associated with reasons for clinical trial stoppage Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues. These results support the growing use of human genetics to ...

Genetics study on COVID-19

Large genetic study on severe COVID-19 Bonn researchers confirm three other genes for increased risk in addition to the known TLR7 gene Whether or not a person becomes seriously ill with COVID-19 depends, among other things, on genetic factors. With this in mind, researchers from the University Hospital Bonn (UKB) and the University of Bonn, in cooperation with other research teams from Germany, the Netherlands, Spain and Italy, investigated a particularly large group of affected individuals. They confirmed the central and already known role of the TLR7 gene in severe courses of the disease in men, but were also able to find evidence for a contribution of the gene in women. In addition, they were able to show that genetic changes in three other genes of the innate immune system contribute to severe COVID-19. The results have now been published in the journal " Human Genetics and Genomics Advances ". Even though the number of severe cases following infection with the SARS-CoV-...