New multi-disciplinary approach sheds light on the role of mitochondrial DNA mutations in cancer

(MEMPHIS, Tenn. – September 10, 2025) 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,” said corresponding author Mondira Kundu, MD, PhD, St. Jude Department of Cell & Molecular Biology. “These different patterns can have dramatically different effects on how cells function.”

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.”

Authors and funding

The study’s first author is Kelly McCastlain, St. Jude. The study’s co-second authors are Catherine Welsh, Rhodes College, and Yonghui Ni and Liang Ding, St. Jude. The study’s other authors are Melissa Franco and Konstantin Khrapko, Northeastern University; Veronica Gonzalez-Pena and Charles Gawad, Stanford University; and Ti-Cheng Chang, Robert Autry, Besian Sejdiu, Qingfei Pan, Wenan Chen, Huiyun Wu, Patrick Schreiner, Sasi Arunachalam, Joung Hyuck Joo, Samuel Brady, Jinghui Zhang, William Evans, Madan Babu, Jiyang Yu, Gang Wu and Stanley Pounds, St. Jude.

The study was supported by the National Institutes of Health (R01GM132231, R01GM134382, R01CA36401, P50GM115279 and U01GM92666), the National Cancer Institute (CA21765) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.

St. Jude Media Relations Contact

Chelsea Bryant 
Desk: (901) 595-0564
Cell: (256) 244-2048
chelsea.bryant@stjude.org
media@stjude.org

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 Progress: A Digital Magazine and follow St. Jude on social media at @stjuderesearch.  

END