{"doi":"10.1681/asn.2020040467","title":"Mitochondria Matter: A Critical Role of ADCK4 in Stabilizing the CoQ Complex in Podocytes in Steroid-Resistant Nephrotic Syndrome","abstract":"Podocytes are a key component of the glomerular filtration barrier, and their dysfunction is central to the underlying pathophysiology of glomerular diseases. In humans, the mutations associated with steroid-resistant nephrotic syndrome (SRNS) or FSGS affect podocyte actin cytoskeleton proteins and the slit diaphragm,1 supporting the view that podocytes are causally related to disease development. Interestingly, a group of mutations in genes involved in coenzyme Q10 (CoQ10; ubiquinone) biosynthesis, such as COQ6; COQ2; prenyl diphosphate synthase, subunit 2 (PDSS2); and ADCK4 (COQ8B), have also been associated with childhood-onset FSGS and SRNS. CoQ10 is a component of the mitochondrial inner membrane and plays important roles in supporting electron transport of oxidative phosphorylation (OXPHOS), protection from oxidative stress, and activation of mitochondrial enzymes required in metabolic pathways, including pyrimidine synthesis.2 Disruption of CoQ10 biosynthesis in podocytes supports the view that mitochondrial function is crucial for the maintenance and function of the glomerular filtration barrier.3 Mitochondria are critical for cellular metabolism, homeostasis, and initiation of apoptosis. Beyond ATP production, mitochondria maintain ion homeostasis; produce precursors for macromolecules, such as lipids, proteins, and DNA; and generate as well as sequester potentially damaging metabolic byproducts such as ammonia and reactive oxygen species (ROS). They also play active roles in integrating signaling pathways and responses to stressors, and are dynamic, with these functions being tightly linked to their form, fission and fusion, motility, and positioning. Considering that podocytes harbor an actin-based cytoskeleton with a contractile machinery that allows for rapid cell shape remodeling and movement, as well as maintaining a very high surface area,4 it would suggest that podocytes need high metabolic activity for function under constant physical forces. However, a recent study indicates that anaerobic glycolysis represents the predominant energy source of podocytes, independent from mitochondrial energy sources under physiologic conditions.5 Hence, the perceived critical role of mitochondria as an energy source for podocyte function is currently debated. In this issue of JASN, a study by Widmeier et al.6 demonstrates that Adck4 function is required for podocyte maintenance and homeostasis in mice by stabilizing the CoQ complex (Figure 1). Using whole-exome sequencing in patients with SRNS, this group was first to identify homozygous loss-of-function mutations in ADCK4 as disease causative.7ADCK4 encodes the aarF domain containing kinase 4, which localizes specifically to mitochondria within foot processes of rat podocytes. In this study, the authors generated a podocyte-specific Adck4 knockout mice (Adck4ΔPodocyte) to examine the pathogenic mechanisms involved. These mice developed albuminuria at 4 months. By 10 months, the kidneys presented abnormal glomeruli with significant fibrosis, disturbed podocyte morphology with severe foot process effacement, and disorganization of the filtration slit. As the mice aged, abnormal mitochondria characterized by hyperproliferation and increased size were identified in podocytes. Overall, the glomerular phenotype of Adck4ΔPodocyte mice recapitulated aspects of the pathology of FSGS in humans resulting from ADCK4 mutations.Figure 1.: Adck4 function is required for podocyte maintenance and homeostasis by stabilizing the CoQ complex. Podocyte specific Adck4 ablation in mice resulted in disturbed podocyte morphology with severe foot process effacement, disorganization of the filtration slit, abnormally large and dysfunctional mitochondria and reduced CoQ10. 2,4-diHB treatment restored CoQ10, mitochondrial function, improved podocytes morphology and prevented foot process effacement. Levels of CoQ10 were decreased in individuals with ADCK4 mutations,7 as well as in Adck4ΔPodocyte mice, ","journal":"Journal of the American Society of Nephrology","year":2020,"id":85192,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":284302,"name":"Ilse S. Daehn","orcid":"0000-0001-9915-5376","position":0,"is_corresponding":true}],"reference_count":14,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:56:02.794896Z","pmid":"32381602","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}