OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Bernd Schöpf, Hansi Weissensteiner, Georg Schäfer, Federica Fazzini, Pornpimol Charoentong, Andreas Naschberger, Bernhard Rupp, Liane Fendt, Valesca Bukur, Irina Giese, Patrick Sorn, Ana Carolina Sant’Anna-Silva, Javier Iglesias-Gonzalez, Ugur Sahin, Florian Kronenberg, Erich Gnaiger and Helmut Klocker ()
Additional contact information
Bernd Schöpf: Medical University Innsbruck, Schöpfstraße 41
Hansi Weissensteiner: Medical University Innsbruck, Schöpfstraße 41
Georg Schäfer: Medical University Innsbruck, Müllerstraße 44
Federica Fazzini: Medical University Innsbruck, Schöpfstraße 41
Pornpimol Charoentong: University Hospital and German Cancer Research Center (DKFZ) Heidelberg, Im Neuenheimer Feld 267
Andreas Naschberger: Medical University Innsbruck, Schöpfstraße 41
Bernhard Rupp: Medical University Innsbruck, Schöpfstraße 41
Liane Fendt: Medical University Innsbruck, Schöpfstraße 41
Valesca Bukur: TRON, Translationale Onkologie an der Universitätsmedizin der Johannes-Gutenberg-Universität Mainz gGmbH, Freiligrathstraße 12
Irina Giese: TRON, Translationale Onkologie an der Universitätsmedizin der Johannes-Gutenberg-Universität Mainz gGmbH, Freiligrathstraße 12
Patrick Sorn: TRON, Translationale Onkologie an der Universitätsmedizin der Johannes-Gutenberg-Universität Mainz gGmbH, Freiligrathstraße 12
Ana Carolina Sant’Anna-Silva: Medical University Innsbruck, Innrain 66/6
Javier Iglesias-Gonzalez: Oroboros Instruments GmbH, Schöpfstraße 18
Ugur Sahin: TRON, Translationale Onkologie an der Universitätsmedizin der Johannes-Gutenberg-Universität Mainz gGmbH, Freiligrathstraße 12
Florian Kronenberg: Medical University Innsbruck, Schöpfstraße 41
Erich Gnaiger: Medical University Innsbruck, Innrain 66/6
Helmut Klocker: University Hospital for Urology, Division of Experimental Urology, Department of Surgery, Medical University Innsbruck, Anichstraße 35

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.

Date: 2020
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DOI: 10.1038/s41467-020-15237-5

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