Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione
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Gerrit Kürschner1,2,*, Qingzhou Zhang3,*, Rosanna Clima4,5, Yi Xiao1,6, Jonas Felix Busch7, Ergin Kilic8, Klaus Jung7,9, Nikolaus Berndt10, Sascha Bulik10, Hermann-Georg Holzhütter10, Giuseppe Gasparre5, Marcella Attimonelli4, Mohan Babu3 and David Meierhofer1
1Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany
2Technical University of Berlin, Institute of Bioanalytics, Department of Biotechnology, Berlin, Germany
3University of Regina, Department of Biochemistry, Regina, Canada
4University of Bari, Department of Biosciences, Biotechnology and Biopharmaceutics, Bari, Italy
5Department of Medical and Surgical Sciences-DIMEC, Medical Genetics Unit, University of Bologna, Bologna, Italy
6Freie Universität Berlin, Fachbereich Biologie, Chemie, Pharmazie, Berlin, Germany
7University Hospital Charité, Department of Urology, Berlin, Germany
8University Hospital Charité, Institute of Pathology, Berlin, Germany
9Berlin Institute for Urologic Research, Berlin, Germany
10Charité University Medicine Berlin, Institute of Biochemistry Computational Systems Biochemistry Group, Berlin, Germany
*These authors have contributed equally to this work
David Meierhofer, email: Meierhof@molgen.mpg.de
Mohan Babu, email: email@example.com
Keywords: renal oncocytoma; complex I deficiency; glutathione metabolism; mtDNA mutation
Received: July 10, 2017 Accepted: September 21, 2017 Published: November 11, 2017
Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD+, NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.
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