OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation.
Nat Commun
; 11(1): 1487, 2020 03 20.
Article
em En
| MEDLINE
| ID: mdl-32198407
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosforilação Oxidativa
/
Próstata
/
Neoplasias da Próstata
/
DNA Mitocondrial
/
Ácido Succínico
/
Mutação
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
/
Male
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Áustria