mtDNA mutations increase tumorigenicity in prostate cancer

Area of Science:

• Mitochondrial genetics
• Cancer biology
• Oncology

Background:

• Mitochondrial DNA (mtDNA) mutations are increasingly recognized as contributors to various cancers.
• Prostate cancer etiology involves complex genetic and environmental factors, with a potential role for mtDNA mutations.

Purpose of the Study:

• To investigate the prevalence and impact of mitochondrial DNA (mtDNA) mutations, specifically in the cytochrome oxidase subunit I (COI) and ATP6 genes, in prostate cancer.
• To determine if pathogenic mtDNA mutations contribute to increased reactive oxygen species (ROS) production and enhanced tumor growth in prostate cancer models.

Main Methods:

• Analysis of COI gene mutations in prostate cancer patients and controls.
• Identification of heteroplasmic mtDNA mutations and germ-line ATP6 mutations in tumors.
• Introduction of a pathogenic mtDNA ATP6 T8993G mutation into prostate cancer cells (PC3) via cybrid transfer.
• Assessment of tumor growth and ROS production in nude mice xenografts.

Main Results:

• 11-12% of prostate cancer patients harbored COI mutations altering conserved amino acids, compared to <2% in controls.
• Four conserved COI mutations were found in multiple independent patients.
• Mutant cybrids carrying the ATP6 T8993G mutation generated tumors 7 times larger than wild-type cybrids and exhibited significantly higher ROS levels.

Conclusions:

• Both germ-line and somatic mtDNA mutations contribute to prostate cancer development.
• mtDNA mutations that impair oxidative phosphorylation can increase ROS production, promoting tumorigenicity.
• mtDNA mutations play a significant role in the etiology of prostate cancer.