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 HIF1α intensify the MSR, redirect amino acids to one carbon metabolism, and facilitate the biosynthesis of reduced glutathione. 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