Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione.

Gerrit Kürschner,Yi Xiao,David Meierhofer,Rosanna Clima,Jonas Felix Busch,Qingzhou Zhang,Mohan Babu,Sascha Bulik,Ergin Kilic,Nikolaus Berndt,Giuseppe Gasparre,Marcella Attimonelli,Klaus Jung,Hermann-Georg Holzhütter

doi:10.18632/oncotarget.22413

Abstract

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.

Highlights

Renal oncocytomas classified as benign renal epithelial neoplasms [1, 2] that are derived from intercalated cells comprise only a small subset (3% to 9%) of all primary renal neoplasms, and can be cured by nephrectomy
While the “mutational signature” C>T has been found in all cancer types and is www.impactjournals.com/oncotarget the resultant of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine [18], the correlation of C>T transitions with age [19] is indicative of a slow growth of renal oncocytoma
Identification of pathogenic low level heteroplasmic mitochondrial DNA (mtDNA) mutations in renal oncocytomas Since oncocytomas with mtDNA mutations feature respiratory defects [4], we examined the assembly of mitochondrial whole exome sequencing (WES) reads and found adequate coverage and quality for a reliable mtDNA reconstruction and variant calling (Supplementary Table 6)

Summary

Introduction

Renal oncocytomas classified as benign renal epithelial neoplasms [1, 2] that are derived from intercalated cells comprise only a small subset (3% to 9%) of all primary renal neoplasms, and can be cured by nephrectomy. The hallmark of renal oncocytomas is the accumulation of mitochondria [3] and the highly diminished or complete loss of complex I (CI) enzyme activity within the electron transport chain [4, 5]. Most mtDNA mutations detected in renal oncocytomas are well above the threshold for a pathogenic phenotype. The level of heteroplasmy can vary between cells in the same tissue or organ, and the proportion of mutant mtDNA determines the penetrance and severity of disease expression [7]. Why and how mutated mtDNA accumulates in oncocytomas still remains unclear

Results

Discussion

Conclusion