Gnaiger 2017 Abstract EUROMIT2017 Cologne
Again not a Warburg effect - mitochondrial function in primary prostate cancer.
Event: EUROMIT2017 Cologne DE
Reprogramming of metabolism is a hallmark of cancer. Defects in mitochondrial energy metabolism have been considered to play a causal role in malignant disease development. This ‘Warburg effect’, however, is neither a general feature of cancer cells nor of malignant tissue. We studied oxidative phosphorylation (OXPHOS) by high-resolution respirometry (HRR) in immortalized prostate epithelial and fibroblast cell lines, and compared mitochondrial function in the benign and malignant tissue of origin, using fresh prostate biopsy samples of only 2 mg wet weight from 50 prostate cancer patients. The cell lines represented the bioenergetic properties of tissue to a limited extent only. Benign tissue showed a higher oxidative capacity with succinate and glutamate, whereas pyruvate was a substrate supporting significantly higher respiratory activities in cell lines. HRR uncovered a reduced respiratory capacity with glutamate as a fuel substrate in malignant versus benign prostate tissue. Based on whole mtDNA sequencing, a significantly higher mutation load was observed in tumor tissue compared to the non-malignant counterpart. Heteroplasmy levels of potentially deleterious mutations in mtDNA encoded genes correlated significantly with reduced glutamate&malate-supported respiration. With pyruvate as a substrate that is formed in glycolysis, however, OXPHOS capacity was fully restored in the cancer tissue. Similarly, succinate as a substrate formed in the tricarboxylic acid cycle compensated for the respiratory deficiency with glutamate. More than revealing a simple mitochondrial defect, these results indicate a compensatory or adaptive metabolic reprogramming and shift of preferred substrate utilization. Combining the flexibility of cell culture models and tissue samples for respirometric analysis are powerful tools for investigation of the versatility of mitochondrial function in response to physiological and pathological challenges, indicating metabolic reprogramming of mitochondrial pathways beyond the Warburg effect.
Labels: MiParea: Respiration, mtDNA;mt-genetics Pathology: Cancer
Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell, Genital, Fibroblast
Coupling state: OXPHOS, ET Pathway: N, S, NS HRR: Oxygraph-2k
- Schöpf B(1), Schäfer G(2,3), Weber A(2), Talasz H(4), Eder IE(2), Klocker H(2), Gnaiger E(5)
- Div Genetic Epidemiol, Dept Medical Genetics, Molec Clin Pharmacol
- Div Exp Urol, Dept Urol
- Dept Pathol
- Biocenter, Sec Clin Biochem
- Dept General Transplant Surgery, D. Swarovski Res Lab
- Medical Univ Innsbruck, Austria. - [email protected]
References and Support
- Tan et al (2015) Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab 21:81-94.
- Schöpf B, Schäfer G, Weber A, Talasz H, Eder IE, Klocker H, Gnaiger E (2016) Oxidative phosphorylation and mitochondrial function differ between human prostate tissue and cultured cells. FEBS J 283:2181-96.