Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

Summary Chromophobe renal cell carcinomas (chRCC) are derived from intercalated cells of the collecting duct system, and are thought to be the malignant counterpart of benign renal oncocytomas. Here, we report the characterization of nine chRCC with adjacent healthy kidney tissues by applying proteome-, transcriptome (TCGA)-, and metabolome profiling. Most strikingly, the reactive oxygen species scavenger glutathione was significantly elevated in chRCC, caused by down-regulated enzymes involved in glutathione degradation. Metabolic reprogramming including stalled gluconeogenesis, down-regulated fatty acid- and amino acid metabolism was identified, even though, the abundance of amino acids and “energy carrier” molecules were unchanged. A striking anti-correlation of the mitochondrial respiratory chain between the transcriptome and the proteome was discovered, the transcripts coding for the respiratory chain were up-, while corresponding proteins and enzymatic activities were down-regulated. Similar to renal oncocytomas, chRCC exhibited a significant increase in glutathione, but are distinguishable by distinct regulation of the respiratory chain.