Schoepf 2018 33rd Annual EAU Congress Copenhagen
| Shift of mitochondrial oxidative phosphorylation is associated with mtDNA mutational load in
primary prostate cancer tissue.
Link: Open Access
Reprogramming of metabolism is a hallmark of cancer. Mitochondria provide energy by oxidative phosphorylation (OXPHOS), supply starting products for cell components and are centrally involved in the execution of apoptosis. There is evidence that mitochondrial malfunction contributes to cancer development and progression. In this study we performed a combined analysis of mitochondrial respiratory function and mitochondrial DNA (mtDNA) mutations in primary prostate cancer tissue.
Mitochondrial respiration of fresh malignant and non-malignant prostate tissue samples obtained from cancer patients undergoing radical prostatectomy was analyzed by high-resolution respirometry in an Oroboros Oxygraph-2k by applying a previously developed substrate/uncoupler/inhibitor titration protocol (Schöpf et al. FEBS J, 2016, doi: 10.1111/febs.13733). mtDNA mutations were assessed by next generation sequencing (NGS) on an Ion Torrent Proton platform and analyzed using our mtDNA-Server tool (Weissensteiner et al, Nucleic Acids Res, 2016, doi: 10.1093/nar/gkw247).
Paired benign and malignant samples of 50 prostate cancer patients were included. High-resolution respirometry uncovered a significantly reduced respiratory capacity with glutamate as a fuel substrate accompanied by a preferred utilization of pyruvate and succinate in malignant tissue samples. With mtDNA NGS (mean coverage 10.085x) 39 (78%) of the malignant tissue samples harbored heteroplasmic sites compared to only 21 (42%) in the corresponding benign tissue. Also, the mtDNA mutation load was significantly higher in tumor tissue compared to the benign counterpart. In total, we detected 93 nucleotide variants in malignant samples, 26 (28%) thereof with heteroplasmy (HP) levels >0.2, compared to 35 variants in the benign samples with only 4 (11%) HPs exceeding allele frequency levels >0.2. The load of non-synonymous, potentially deleterious HPs in protein-coding mt-genes was associated with a significant shift from glutamine and malate to succinate and pyruvate-fueled oxidative phosphorylation capacity. In the malignant tissue, HP levels lower than 0.1 (N=26) were associated with a 25% decrease and HP levels of greater 0.1 (N=13) with a 35% decrease in glutamine-fueled respiration capacity in comparison to samples carrying no HPs (N=24). No statistically significant correlation of mt-DNA mutational burden was found to tumor Gleason scores or patients’ PSA levels, however, samples exhibiting a TMPRSS-ERG gene fusion showed higher mtDNA mutations rates compared to the wild-type counterparts.
We identified significant alterations of mitochondrial respiration and mt-DNA mutations in primary prostate cancer compared to the benign tissue of origin. Our data uncover a shift of oxidative mitochondrial respiratory capacity, which is associated with increased mtDNA heteroplasmy load.
• Bioblast editor: Kandolf G
Labels: MiParea: Respiration, mtDNA;mt-genetics, mt-Medicine Pathology: Cancer
Organism: Human Tissue;cell: Genital Preparation: Permeabilized cells, Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: F, N, NS, Other combinations, ROX HRR: Oxygraph-2k