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

Proc Natl Acad Sci U S A
Authors
Keywords
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 ) 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.

Year of Publication
2018
Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
27
Pages
E6283-E6290
Date Published
2018 07 03
ISSN
1091-6490
DOI
10.1073/pnas.1711888115
PubMed ID
29915083
PubMed Central ID
PMC6142220
Links
Grant list
P30 DK040561 / DK / NIDDK NIH HHS / United States
P50 CA101942 / CA / NCI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States