How APOL1 Mutations Impact Mitochondrial Function in Kidney Disease Revealed by Organoid Models

Recent groundbreaking research utilizing kidney organoids has shed light on the role of genetic mutations in the development of chronic kidney disease (CKD). CKD affects over 700 million individuals worldwide and is influenced by a combination of genetic, environmental, and medical factors. Notably, mutations in the APOL1 gene are significant genetic risk factors, especially prevalent among individuals of West African descent, where up to 13% carry risk variants and 38% are carriers.

To better understand how these mutations contribute to kidney disease, researchers from the University of Leiden in the Netherlands, led by Siebe Spijker, generated stem cells from skin biopsies of patients with APOL1-associated kidney disease. These stem cells were then differentiated into kidney organoids—miniature, lab-grown structures that mimic many aspects of actual kidney tissue. By employing genetic engineering techniques, the team corrected APOL1 mutations within some organoids to compare their functions.

The study, published in Stem Cell Reports, employed various laboratory tests demonstrating that APOL1 mutations disrupt mitochondrial function—the cell’s energy-producing structures—in kidney cells. Specifically, podocytes, key cells in the kidney’s filtration system, showed heightened vulnerability, especially under stress conditions involving inflammatory proteins. This insight suggests that inflammation, often resulting from viral infections or autoimmune diseases, may trigger or exacerbate APOL1-related kidney problems.

Spijker and his team highlighted that the human kidney organoid model could accelerate drug discovery for APOL1-associated kidney disease, a condition difficult to study in animals since APOL1 is not naturally expressed in rodents. The findings suggest that mutant APOL1 proteins impair mitochondrial respiration in podocytes, leading to cellular dysfunction and contributing to disease progression.

This research points toward potential therapeutic strategies targeting mitochondrial health and emphasizes the importance of inflammation control in managing APOL1-related kidney conditions. Overall, these insights provide a promising avenue for developing targeted treatments aimed at mitigating kidney damage caused by genetic mutations.

Source: https://medicalxpress.com/news/2025-10-kidney-organoids-reveal-apol1-mutations.html