Mitochondria can affect cancer severity, research shows, with the copy number of its DNA correlating with the extent of genetic mutation in cancer cells.
The findings, in The Febs Journal, may shed light on the role of mitochondrial (mt)DNA and the functional states of these organelles in the progression of cancer.
“Our results reveal a close association of mtDNA copy number with cancer progression and therapy response,” said researcher Riddhiman Dhar, PhD, who co-authored the paper with his colleague Anamika Acharyya, PhD, at the the Indian Institute of Technology Kharagpur.
“These findings could pave the way for deeper investigations into the role of mitochondria in cancer that will enable new cancer management strategies.”
Mitochondria have a central role in vital cellular processes including energy generation, metabolism, respiration, iron homeostasis, stress response, and apoptosis.
While most of the proteins needed for them to function properly as encoded in the nuclear DNA of cells, mitochondria also harbor their own DNA in multiple copies, which encodes 13 essential proteins.
The copy number of this mtDNA determines the functional state of mitochondria, thereby affecting cellular energy production, growth, metabolism, and response to stress.
While variations in this copy number have been seen across many types of cancer and been linked to changes in gene expression, there is less certainty about how it relates to mutational accumulation in the disease.
The researchers therefore conducted a large-scale analysis of mtDNA copy number, mutations, and gene expression across multiple cancer types from the Pan-cancer Analysis of Whole Genomes dataset.
They found that mtDNA copy number increased in conjunction with mutational load and was a key predictor of mutational load in patients and was linked with differential expression in several genes linked with chemotherapy response.
Cancer samples with low-mtDNA generally had increased expression of cancer-promoting genes, including genes involved in cell migration and epithelial–mesenchymal transition. There was also upregulation of suppressor genes in high-mtDNA samples in several cancer types.
Predictive modeling identified mtDNA copy number and the number of mitochondria-localized genes affected by mutations as the key predictors of expression of several cancer-associated hallmark pathways.
The correlation between mtDNA copy number and mutational load varied across cancer types, the research team noted.
Although tumor ploidy significantly correlated with mtDNA copy number and mutational load, the correlation between mtDNA copy number and mutational load remained after adjusting for the effect of ploidy.
“These results revealed that tumor ploidy can influence mtDNA copy number in cancer patients to some extent but cannot fully explain the variation in mtDNA copy number or its correlation with mutational load,” the researchers pointed out.
Overall, they concluded: “Taken together, these results suggest major implications of mtDNA copy number variation and the corresponding variation in mitochondrial functional state for cancer progression.
“These findings open up avenues for a deeper understanding of the role of mitochondria in cancer, which could provide new disease management strategies in future.”
