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, Helmut Klocker

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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.
Original languageEnglish (US)
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Chemistry
  • General Physics and Astronomy

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