1. Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease.
- Author
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Sidhom, Eriene-Heidi, Choah Kim, Kost-Alimova, Maria, Theng Ting, May, Keller, Keith, Avila-Pacheco, Julian, Watts, Andrew J. B., Vernon, Katherine A., Marshall, Jamie L., Reyes-Bricio, Estefanía, Racette, Matthew, Wieder, Nicolas, Kleiner, Giulio, Grinkevich, Elizabeth J., Fei Chen, Weins, Astrid, Clish, Clary B., Shaw, Jillian L., Quinzii, Catarina M., and Greka, Anna
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BRAF genes , *MITOGEN-activated protein kinases , *KIDNEY diseases , *UBIQUINONES , *UNSATURATED fatty acids , *ENZYME deficiency , *DRUG delivery systems , *RESEARCH , *HETEROCYCLIC compounds , *MITOCHONDRIAL pathology , *ANIMAL experimentation , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *MUSCLE weakness , *HYDROCARBONS , *CELLULAR signal transduction , *COMPARATIVE studies , *TRANSFERASES , *RESEARCH funding , *EPITHELIAL cells , *LIPID peroxidation (Biology) , *ATAXIA , *MICE - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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