OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation.
DNA, Mitochondrial
/ genetics
Electron Transport Complex I
/ metabolism
Energy Metabolism
High-Throughput Nucleotide Sequencing
Humans
Malates
Male
Mitochondria
/ genetics
Mutation
Oxidation-Reduction
Oxidative Phosphorylation
Prostate
/ metabolism
Prostatic Neoplasms
/ genetics
Succinic Acid
/ metabolism
Transcriptome
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 03 2020
20 03 2020
Historique:
received:
16
12
2016
accepted:
25
02
2020
entrez:
22
3
2020
pubmed:
22
3
2020
medline:
18
7
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32198407
doi: 10.1038/s41467-020-15237-5
pii: 10.1038/s41467-020-15237-5
pmc: PMC7083862
doi:
Substances chimiques
DNA, Mitochondrial
0
Malates
0
malic acid
817L1N4CKP
Succinic Acid
AB6MNQ6J6L
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1487Commentaires et corrections
Type : CommentIn
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