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...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	Nature communications Ročník 11; číslo 1; s. 1487 - 16
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 20.03.2020 Nature Publishing Group Nature Portfolio
Predmet:	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
On-line prístup:	Získať plný text
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-15237-5