Impact of mitochondrial alterations on prostrate cancer progression

Abstract

Cancer metabolism is characterised by a ‘Warburg shift’ to aerobic glycolysis with decreased mitochondrial oxidative phosphorylation (OXPHOS), feasibly mediated by alterations in mitochondrial DNA (mtDNA). However, despite recent advances in our understanding of nuclear genomic alterations in prostate cancer, there remains a paucity of data evaluating the impact of mitochondrial alterations in prostate cancer progression. Therefore, using publicly available genomic datasets, the mitochondrial molecular landscape of aggressive prostate cancer was characterized. This revealed a spectrum of mtDNA mutations under clonal selection pressures, reduced mtDNA copy number, and a transcriptomic profile composed of reduced mitochondrial and increased nuclear OXPHOS gene expression. In order to assess the downstream impact of these alterations and aid clinical translation, I developed an automated assay to evaluate proteomic OXPHOS defects in archived prostate cancer tissue microarrays at the single cell level. Upon unpicking widespread multi-faceted heterogeneity in OXPHOS protein expression, patients with low complex I abundance and increased mitochondrial mass appeared to be at increased risk of all-cause mortality at 20- year follow-up. The prognostic value of both mitochondrial molecular alterations and proteomic OXPHOS defects was enriched in patients with PTEN-loss and TMPRSS2:ERG fusion. Given that mitochondrial alterations and prostate cancer risk features are also associated with advancing age, transgenic models were generated to elucidate the impact of age-related systemic mitochondrial dysfunction on PTEN-deficient prostate cancer progression. Despite early mortality due to accelerated age-related phenotypes, attenuated tumour progression was observed, suggesting a tumour suppressive effect of systemic mitochondrial dysfunction. In conclusion, mitochondrial alterations exert diverse systemic and local effects on prostate cancer progression. Leveraging mitochondrial tissue biomarkers and mitochondrial-targeted systemic therapies may provide a novel approach for identifying aggressive prostate cancer and suppressing progression to lethal disease.