New method reveals how mitochondrial DNA mutations influence cancer growth

Mitochondria act as energy factories in cells and have their own, separate DNA. Mutations to mitochondrial DNA (mtDNA) have been observed in cancer, but it has been unclear how these changes might affect cancer growth. To find answers, St. Jude Children's Research Hospital scientists combined computational tools and DNA sequencing technologies to examine these mtDNA mutations in cancer cells closely. Their new method lets scientists pinpoint when these mutations occur, how they change as cancer develops and whether they affect how cancer cells behave. The results of this study were published today in Science Advances.

Exploring the role that individual mtDNA mutations have on cancer has historically been difficult.

Each cell contains hundreds of copies of mitochondrial DNA; so, a mutation might be present at low levels in many cells, or at high levels in just a subset of cells. These different patterns can have dramatically different effects on how cells function."

Mondira Kundu, MD, PhD, corresponding author, St. Jude Department of Cell & Molecular Biology

mtDNA mutations are not random passengers in cancer

To overcome this challenge, the team combined several techniques, including powerful computational tools, statistical analyses, bulk whole genome sequencing and single-cell studies. This approach allowed them to determine how much mitochondrial DNA was mutated in each cell, and when these changes happened in relation to cancer development. Surprisingly, the researchers found that some mitochondrial DNA mutations occur before a cell turns cancerous - and that these mutations are not always random. It appears that in some cases, cancer cells actively "select" for a mix of normal and mutated mitochondrial DNA.

"This approach allowed us to tell apart harmless 'passenger' mutations from those that may help cancer grow," Kundu explained. "That's something the field has struggled with until now."

Kundu's team took the analysis further by deploying a tool, called NetBID2, created by co-author Jiyang Yu, PhD, St. Jude Department of Computational Biology interim chair. With this tool, the researchers found evidence that mtDNA may contribute to therapy resistance. They discovered a mtDNA mutation linked to changes in pathways associated with resistance to glucocorticoids, a common therapy for acute lymphoblastic leukemia. Further analysis suggested that this type of mitochondrial mutation may make leukemia cells more likely to resist treatment.

While this research highlights the role mitochondrial DNA mutations might play in leukemia, the main achievement is the creation of a novel multidimensional approach to investigate mtDNA. Kundu is optimistic about the value of digging deeper into this overlooked feature of cancer growth. 

"This work shows that mitochondrial DNA can influence both how leukemia starts and how it progresses," said Kundu. "The next important step is to apply this approach to many more patient samples, so we can fully understand its impact."