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Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease
Eriene-Heidi Sidhom1,2, Choah Kim1,2, Maria Kost-Alimova2
1Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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.
Insights
Mitochondrial coenzyme Q (CoQ) deficiency in kidney podocytes disrupts polyunsaturated fatty acid metabolism and the Braf/Mapk pathway, not the electron transport chain. Targeting this pathway may treat kidney disease.
Area of Science:
- Mitochondrial biochemistry
- Cell biology
- Nephrology
Background:
- Mutations in coenzyme Q (CoQ) biosynthesis cause kidney failure via podocyte loss.
- Tubular epithelial cells are spared despite higher mitochondrial content, suggesting cell-specific CoQ roles.
- Noncanonical, electron transport chain (ETC)-independent functions of CoQ are unexplored.
Purpose of the Study:
- To investigate cell-specific, ETC-independent roles of CoQ in podocytes.
- To identify molecular pathways affected by CoQ deficiency in kidney disease.
- To explore therapeutic targets for CoQ-related kidney failure.
Main Methods:
- Utilized Pdss2 enzyme deficiency in podocytes to induce CoQ depletion in mice.
- Employed single-nucleus RNA-Sequencing (snRNA-Seq) to analyze kidney tissue from Pdss2kd/kd mice.
- Administered GDC-0879, a Braf/Mapk inhibitor, to treat affected mice.
- Conducted mechanistic studies in vitro and confirmed findings in vivo.
- Analyzed gene expression patterns in human kidney disease patient tissues.
Main Results:
- CoQ depletion in podocytes perturbed polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway, independent of ETC dysfunction.
- snRNA-Seq revealed a podocyte-specific Braf/Mapk pathway perturbation in nephrotic syndrome.
- Braf/Mapk pathway inhibition with GDC-0879 ameliorated kidney disease in Pdss2kd/kd mice.
- A novel PUFA metabolism perturbation was identified in Pdss2-depleted podocytes and confirmed in vivo.
- GPX4, an antioxidant enzyme, was elevated during disease and normalized upon Braf/Mapk inhibition.
Conclusions:
- Coenzyme Q has critical ETC-independent roles in podocyte function.
- The Braf/Mapk pathway is a key mediator of CoQ deficiency-induced kidney podocyte injury.
- PUFA metabolism is a novel, affected pathway in CoQ-related kidney disease.
- Targeting the Braf/Mapk pathway offers a potential therapeutic strategy for kidney diseases.
- Observed gene expression patterns in human kidney disease suggest broader relevance.
