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

Bernd Schöpf,Valesca Bukur,Pornpimol Charoentong,Helmut Klocker,Ana Carolina Sant’Anna-Silva,Ugur Sahin,Patrick Sorn,Florian Kronenberg,Georg Schäfer,Liane Fendt,Bernhard Rupp,Javier Iglesias-Gonzalez,Hansi Weissensteiner,Andreas Naschberger,Erich Gnaiger,Federica Fazzini,Irina Giese

doi:10.1038/s41467-020-15237-5

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.

Highlights

Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression
While the majority of electron transfer system (ETS) machinery proteins are encoded by nuclear DNA, 13 ETS subunits are encoded by mtDNA, a small circular genome. mtDNA mutations have been linked to Prostate cancer (PCa) formation and progression[6,7]
Our results reveal a shift towards higher oxidation of succinate, which is associated with deleterious mutations in mitochondrial Complex I genes and a rewired expression of mitochondrial metabolic enzymes in primary prostate cancer

Summary

Introduction

Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. 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, in high-grade tumors. 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. Compared to nDNA, mtDNA exhibits a higher mutation rate caused by increased exposure to ETS-derived ROS and less efficient DNA repair[8]. Random segregation and subpopulation replication of mtDNA variants lead to “heteroplasmy” (HP), the presence of different populations of mtDNA variants in a mitochondrion, cell or tissue. mtDNA mutations are frequently found in localized PCa9–12; their functional consequences remain elusive

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