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

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.

Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

“…Multi-omics profiling of pRCC was performed, revealing a fundamental reprogramming of the pathways for gluconeogenesis, the respiratory chain, and for glutathione metabolism. These can be regarded as a general hallmark of kidney tumors, as was previously observed in renal oncocytomas (17), chRCCs (27), and in ccRCCs at the transcript level (28).…”

“…In our previous study on renal oncocytomas, we identified a coordinated up-regulation of proteins of the OXPHOS complexes II-V and the mtDNA, but a striking reduction in the abundance of CI proteins ( Figure 3A) (17). This was explained by several specific low-level heteroplasmic mtDNA mutations of the CI genes in renal oncocytomas.…”

“…The significant reduction of enzymes involved in gluconeogenesis thus has metabolic consequences on multiple layers and is a hallmark of all investigated kidney cancers, such as in pRCC (this study), ccRCC (28), chRCC (27), and renal oncocytomas (17). By abandoning this endergonic pathway in pRCC the tumor is able to simultaneously reduce other processes involved in the generation of ATP.…”

Metabolic modelling of kidney diseases: Lessons learned from the liver

“…28 Multi-compartment models and models based on partial differential equations are available to compute the distribution and excretion of substances such as FDG, 33 drugs, 34,35 glucose and lactate 36 and to describe the regulation of renal salt and water excretion, glomerular blood flow, filtration rates and blood flow. 39 , represents an efficient way to generate metabolic cell models that can be integrated into existing tissue-scale models of the kidney. Similar to the liver, renal epithelial enzyme patterns vary considerably, including reciprocal capacities of gluconeogenesis and glycolysis in tubule cells resident in the cortex and the medulla.…”

“…38 Owing to the high similarities shared between the central metabolism of hepatocytes and renal tubule cells, re-parameterization of complex kinetic liver models 14 with kidney-specific parameters, as has been done in Ref. 39 , represents an efficient way to generate metabolic cell models that can be integrated into existing tissue-scale models of the kidney.…”