Early loss of mitochondrial complex I and rewiring of glutathione metabolism in renal oncocytoma

Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6283-E6290. doi: 10.1073/pnas.1711888115. Epub 2018 Jun 18.

Abstract

Renal oncocytomas are benign tumors characterized by a marked accumulation of mitochondria. We report a combined exome, transcriptome, and metabolome analysis of these tumors. Joint analysis of the nuclear and mitochondrial (mtDNA) genomes reveals loss-of-function mtDNA mutations occurring at high variant allele fractions, consistent with positive selection, in genes encoding complex I as the most frequent genetic events. A subset of these tumors also exhibits chromosome 1 loss and/or cyclin D1 overexpression, suggesting they follow complex I loss. Transcriptome data revealed that many pathways previously reported to be altered in renal oncocytoma were simply differentially expressed in the tumor's cell of origin, the distal nephron, compared with other nephron segments. Using a heuristic approach to account for cell-of-origin bias we uncovered strong expression alterations in the gamma-glutamyl cycle, including glutathione synthesis (increased GCLC) and glutathione degradation. Moreover, the most striking changes in metabolite profiling were elevations in oxidized and reduced glutathione as well as γ-glutamyl-cysteine and cysteinyl-glycine, dipeptide intermediates in glutathione biosynthesis, and recycling, respectively. Biosynthesis of glutathione appears adaptive as blockade of GCLC impairs viability in cells cultured with a complex I inhibitor. Our data suggest that loss-of-function mutations in complex I are a candidate driver event in renal oncocytoma that is followed by frequent loss of chromosome 1, cyclin D1 overexpression, and adaptive up-regulation of glutathione biosynthesis.

Keywords: complex I; glutathione; mtDNA; oncocytoma; γ-glutamyl cycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma, Oxyphilic* / genetics
  • Adenoma, Oxyphilic* / metabolism
  • Adenoma, Oxyphilic* / pathology
  • Cell Survival / genetics
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 1 / metabolism
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Electron Transport Complex I / deficiency*
  • Female
  • Gene Expression Profiling
  • Glutathione* / genetics
  • Glutathione* / metabolism
  • Humans
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Male
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondria* / pathology
  • Neoplasm Proteins / deficiency*

Substances

  • CCND1 protein, human
  • DNA, Mitochondrial
  • DNA, Neoplasm
  • Neoplasm Proteins
  • Cyclin D1
  • Electron Transport Complex I
  • Glutathione

Supplementary concepts

  • Oncocytoma, renal