Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

• Published in: The Journal of clinical investigation Vol. 131; no. 5; pp. 1 - 16
• Main Authors: Sidhom, Eriene-Heidi, Kim, Choah, Kost-Alimova, Maria, Ting, May Theng, Keller, Keith, Avila-Pacheco, Julian, Watts, Andrew Jb, Vernon, Katherine A, Marshall, Jamie L, Reyes-Bricio, Estefanía, Racette, Matthew, Wieder, Nicolas, Kleiner, Giulio, Grinkevich, Elizabeth J, Chen, Fei, Weins, Astrid, Clish, Clary B, Shaw, Jillian L, Quinzii, Catarina M, Greka, Anna
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2021
• Subjects: Biomedical research; Biosynthesis; Care and treatment; Cellular signal transduction; Coenzyme Q; Development and progression; Electron transport chain; Enzymes; Epithelial cells; Fatty acids; Gene expression; Genetic aspects; Health aspects; Kidney diseases; Lipid peroxidation; Lipids; Localization; MAP kinase; Metabolism; Mitochondria; Mutation; Nephrotic syndrome; Polyunsaturated fatty acids; Regulation; Renal failure; Ubiquinones; United States; Mitochondria; Nephrology; Chronic kidney disease; Genetic diseases; Cell Biology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci141380

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.