Early loss of mitochondrial complex I and rewiring of glutathione metabolism in renal oncocytoma

Significance Renal oncocytomas are benign kidney tumors with numerous mitochondria. Here, we analyze the mitochondrial (mtDNA) and nuclear genomes of these tumors. Our analysis finds mtDNA mutations in complex I (the first step in mitochondrial respiration) to be early genetic events that likely contribute to tumor formation. Since mtDNA mutations can lead to severe degenerative disorders, the cellular responses allowing renal oncocytoma cells to grow are important to consider. To properly understand authentic gene expression changes in tumors, we found it important to consider the gene expression pattern of the tumor’s cell of origin, the distal nephron. By doing so, we uncover alterations in glutathione synthesis and turnover that likely represent an adaptive metabolic response in renal oncocytoma.