Study: APOL1 Mutations in CKD Significantly Affect Cells Crucial to Kidney Function

Recent research published in Stem Cell Reports shows that apolipoprotein L1 (APOL1) mutations impair mitochondrial function in the kidneys of patients with chronic kidney disease (CKD), leading to impaired respiration and energy production. The authors wrote that these findings pose significant implications in the development of targeted treatments for patients with APOL1-mutated kidney disease (AMKD).^1,2

CKD affects more than 700 million people worldwide and is caused by both genetic and environmental factors in addition to existing medical conditions. One of the known genetic risk factors for CKD includes mutations in APOL1, a particular gene. These are rare in most populations; however, 2 risk variants are present in as many as 13% of West African patients, and another 38% possess 1 copy and are considered carriers of CKD. The causes for AMKD are not well understood, and treatments are lacking.^1,2

This study used induced pluripotent stem cells (iPSCs) that were derived from 2 patients homozygous for G1 and G2 to model human AMKD in kidney organoids. The G1G1 patient had stage 4 CKD, whereas the G2G2 patient had stage 5 CKD with microalbuminuria and kidney disease clinically attributed to hypertension. From these patients, researchers genotyped peripheral blood DNA, and G1 and G2 cells were visually inspected for quality control. Following the successful reprogramming into iPSCs, APOL1 risk variant (RV) sequences were confirmed and generated.¹

The findings showed, using single-cell transcriptomic analysis and immunofluorescence imaging, APOL1 upregulation in patients’ podocytes after interferon-gamma (IFN-γ) treatment. Transcriptomics and spatial dynamic metabolomics demonstrated a noticeable reduction in oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity, along with upregulation of glycolysis and hypoxia signaling in RV podocytes. Furthermore, isolated RV glomeruli revealed there was an increase in maximal respiration rate following treatment with IFN-γ, whereas RV podocytes derived from iPSCs displayed a reduced number of mitochondrial branches and shorter branch length. The authors wrote that this model demonstrates early metabolic reprogramming of RV podocytes in response to inflammatory injury, providing strong evidence that mitochondrial dysfunction may play a pivotal role in the early pathophysiology of AMKD.¹

“In this study, a disease model of AMKD was developed using patient-derived iPSCs with a G1G1 and G2G2 genetic background. Confounding genetic factors were controlled by generating control G0 iPSCs isogenic to G2 using CRISPR-Cas9 gene editing. We detected metabolic dysfunction in APOL1 RV podocytes after IFN-γ treatment; glycolytic flux was increased at the expense of mitochondrial respiration, and mitochondria fragmentation was observed,” the authors wrote.¹

Further, the authors explained that prior research conducted in mice demonstrated that podocytes primarily depend on anaerobic glycolysis under certain physiological conditions. The investigators assessed mitochondrial respiration in glomeruli isolated from organoids and found that the oxygen consumption rate increased in G0 organoids upon IFN-γ exposure, suggesting that while podocytes are usually dependent on glycolysis, the stress response links increased energy demand using OXPHOS, which appears weakened in the context of APOL1 RV. Additionally, monocytes display a similar response to IFN-γ by increasing the respiration rate through reprogramming NAD+ metabolism.¹

“Overall, this study provides valuable insights that point toward mitochondrial impairment as a central driver of the metabolic reprogramming observed in APOL1 RV podocytopathy and a key pathogenic event in AMKD, thereby paving the way for future therapeutic strategies,” the study authors concluded.¹

REFERENCES

1. 1. Song H, Dumas SJ, Wang G, et al. APOL1 risk variants induce metabolic reprogramming of podocytes in patient-derived kidney organoids. Stem Cell Reports. 2025;20(10):102650. doi:10.1016/j.stemcr.2025.102650

2. International Society for Stem Cell Research. Kidney organoid unlocks genetic cause of chronic kidney disease. News release. October 2, 2025. Accessed October 15, 2025. https://www.eurekalert.org/news-releases/1100214