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

Raj K. Gopal, Sarah E. Calvo, Angela R. Shih, Frances L. Chaves, Declan McGuone, Eran Mick, Kerry A. Pierce, Yang Li, Andrea Garofalo, Eliezer M. Van Allen, Clary B. Clish, Esther Oliva, and Vamsi K. Mootha
PNAS July 3, 2018 115 (27) E6283-E6290; published ahead of print June 18, 2018 https://doi.org/10.1073/pnas.1711888115

  1. Contributed by Vamsi K. Mootha, April 17, 2018 (sent for review July 6, 2017; reviewed by Ralph J. DeBerardinis and Robert A. Weinberg)

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Significance

Renal oncocytomas are benign kidney tumors with numerous mitochondria. Here, we analyze the mitochondrial (mtDNA) and nuclear genomes of these tumors. Our analysis finds mtDNA mutations in complex I (the first step in mitochondrial respiration) to be early genetic events that likely contribute to tumor formation. Since mtDNA mutations can lead to severe degenerative disorders, the cellular responses allowing renal oncocytoma cells to grow are important to consider. To properly understand authentic gene expression changes in tumors, we found it important to consider the gene expression pattern of the tumor’s cell of origin, the distal nephron. By doing so, we uncover alterations in glutathione synthesis and turnover that likely represent an adaptive metabolic response in renal oncocytoma.

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.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: vamsi{at}hms.harvard.edu.

  • Author contributions: R.K.G., E.O., and V.K.M. designed research; R.K.G., S.E.C., A.R.S., F.L.C., D.M., K.A.P., A.G., E.M.V.A., C.B.C., and E.O. performed research; R.K.G., S.E.C., A.R.S., E.M., Y.L., A.G., E.M.V.A., C.B.C., and E.O. analyzed data; R.K.G., S.E.C., and V.K.M. wrote the paper; and V.K.M. supervised research.

  • Reviewers: R.J.D., University of Texas-Southwestern Medical Center; and R.A.W., Massachusetts Institute of Technology, The David H. Koch Institute for Integrative Cancer Research.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1711888115/-/DCSupplemental.

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Early loss of mitochondrial complex I and rewiring of glutathione metabolism in renal oncocytoma
Raj K. Gopal, Sarah E. Calvo, Angela R. Shih, Frances L. Chaves, Declan McGuone, Eran Mick, Kerry A. Pierce, Yang Li, Andrea Garofalo, Eliezer M. Van Allen, Clary B. Clish, Esther Oliva, Vamsi K. Mootha
Proceedings of the National Academy of Sciences Jul 2018, 115 (27) E6283-E6290; DOI: 10.1073/pnas.1711888115
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