Activation of the Mitochondrial Stress Response in Clear Cell Renal Cell Carcinoma

Kidneys from our transgenic mouse model of early stage cancer of the kidney (TRACK) exhibit a mitochondrial stress response (MSR) signature, as indicated by increased mRNA for Atf4, a key transcription factor activated in the MSR, and increased transcripts of Atf4 targets, including Asns, Mthfd2, Trib3, Ddit3(Chop;Gadd153), Atf3, Ppp1r15a(Gadd34), Aldh1l2, Fgf21, and Slc20a1. By performing transcriptomics analyses from TRACK versus wild type (WT) kidneys after dietary vitamin A deprivation, we show that both vitamin A deficiency (VAD) and expression of constitutively active HIF1a intensify the MSR, redirect amino acids to one carbon metabolism, and facilitate the biosynthesis of reduced glutathione. Overall design: We performed RNAseq on kidney cortex samples from transgenic mice with constitutive activation of HIF1A and wild type mice fed on a regular chow and vitamin A deficient diet