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Chromophobe renal cell carcinoma (chRCC); Renal oncocytoma (RO); oxidative phosphorylation (OXPHOS); mitochondrial DNA content; glutathione metabolism
Abstract:
Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO) are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in RO but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multi-omic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in RO. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and RO and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy.
