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

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 respi...

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Published in:Nature communications Vol. 11; no. 1; pp. 1487 - 16
Main Authors: Schöpf, Bernd, Weissensteiner, Hansi, Schäfer, Georg, Fazzini, Federica, Charoentong, Pornpimol, Naschberger, Andreas, Rupp, Bernhard, Fendt, Liane, Bukur, Valesca, Giese, Irina, Sorn, Patrick, Sant’Anna-Silva, Ana Carolina, Iglesias-Gonzalez, Javier, Sahin, Ugur, Kronenberg, Florian, Gnaiger, Erich, Klocker, Helmut
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 20.03.2020
Nature Publishing Group
Nature Portfolio
Subjects:
38/39
45/22
45/23
45/90
45/91
49
631/208/514/2254
631/45/320
631/67/589/466
82/1
82/51
82/80
Amino acids
Deoxyribonucleic acid
DNA
DNA, Mitochondrial - genetics
Electron transport chain
Electron Transport Complex I - metabolism
Energy Metabolism
Gene expression
High-Throughput Nucleotide Sequencing
Humanities and Social Sciences
Humans
Malate
Malates
Male
Metabolism
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondrial DNA
multidisciplinary
Mutation
NADH
NADH-ubiquinone oxidoreductase
Nicotinamide adenine dinucleotide
Oxidation
Oxidation-Reduction
Oxidative Phosphorylation
Phenotypes
Prostate - metabolism
Prostate - pathology
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Respiration
Risk analysis
Risk factors
Science
Science (multidisciplinary)
Substrates
Succinic Acid - metabolism
Transcriptome
Tumors
Wiring
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. The re-wiring of the metabolic machinery is a common feature in cancer. Here, the authors show, using paired normal and prostate cancer samples that the cancer samples exhibit a shift to succinate respiration, which is associated with elevated levels of mitochondrial DNA mutations.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-15237-5