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Mitochondria Matter: A Critical fusion, motility, and positioning. Considering that podocytes harbor an actin-based cytoskeleton with a contractile machin- Role of ADCK4 in Stabilizing the ery that allows for rapid cell shape remodeling and movement, as well as maintaining a very high surface area,4 it would sug- CoQ Complex in Podocytes in gest that podocytes need high metabolic activity for function Steroid-Resistant Nephrotic under constant physical forces. However, a recent study in- dicates that anaerobic glycolysis represents the predominant Syndrome energy source of podocytes, independent from mitochondrial energy sources under physiologic conditions.5 Hence, the per- UP FRONT MATTERS Ilse S. Daehn ceived critical role of mitochondria as an energy source for Division of Nephrology, Department of Medicine, Icahn School of podocyte function is currently debated. Medicine at Mount Sinai, New York City, New York In this issue of JASN,astudybyWidmeieret al.6 dem- JASN 31: 1167–1169, 2020. onstrates that Adck4 function is required for podocyte doi: https://doi.org/10.1681/ASN.2020040467 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 homo- Podocytes are a key component of the glomerular filtration zygous loss-of-function mutations in ADCK4 as disease caus- barrier, and their dysfunction is central to the underlying ative.7 ADCK4 encodes the aarF domain containing kinase 4, pathophysiology of glomerular diseases. In humans, the mu- which localizes specifically to mitochondria within foot pro- tations associated with steroid-resistant nephrotic syndrome cesses of rat podocytes. In this study, the authors generated (SRNS) or FSGS affect podocyte actin cytoskeleton a podocyte-specific Adck4 knockout mice (Adck4DPodocyte) and the slit diaphragm,1 supporting the view that podocytes to examine the pathogenic mechanisms involved. These mice are causally related to disease development. developed albuminuria at 4 months. By 10 months, the kidneys Interestingly, a group of mutations in involved in presented abnormal glomeruli with significant fibrosis, dis- coenzyme Q (CoQ ; ubiquinone) biosynthesis, such as 10 10 turbed podocyte morphology with severe foot process efface- COQ6; COQ2; prenyl diphosphate synthase, subunit 2 ment, and disorganization of the filtration slit. As the mice (PDSS2); and ADCK4 (COQ8B), have also been associated aged, abnormal mitochondria characterized by hyperprolifer- with childhood-onset FSGS and SRNS. CoQ is a component 10 ation and increased size were identified in podocytes. Overall, of the mitochondrial inner membrane and plays important the glomerular phenotype of Adck4DPodocyte mice recapitu- roles in supporting electron transport of oxidative phosphor- lated aspects of the pathology of FSGS in humans resulting ylation (OXPHOS), protection from oxidative stress, and ac- from ADCK4 mutations. tivation of mitochondrial required in metabolic Levels of CoQ were decreased in individuals with ADCK4 pathways, including pyrimidine synthesis.2 Disruption 10 mutations,7 as well as in Adck4DPodocyte mice, suggesting that of CoQ biosynthesis in podocytes supports the view that 10 ADCK4 is indeed involved in CoQ biosynthesis. In the ab- mitochondrial function is crucial for the maintenance and 10 sence of Adck4, podocytes had decreased OXPHOS complex function of the glomerular filtration barrier.3 II-III proteins and membrane potential, generating increased Mitochondria are critical for cellular metabolism, homeo- ROS, making podocytes more susceptible to mitochondrial stasis, and initiation of apoptosis. Beyond ATP production, injury compared with other kidney derived cells. Next, the mitochondria maintain ion homeostasis; produce precursors authors discovered that Adck4 interacted with mainly mito- for macromolecules, such as lipids, proteins, and DNA; and chondrial proteins, including CoQ , and that Adck4 ablation generate as well as sequester potentially damaging metabolic 5 in podocytes destabilized the CoQ complex and the cyto- byproducts such as ammonia and reactive species skeleton. The investigators used 2,4-dihydroxybenzoic acid (ROS). They also play active roles in integrating signaling (2,4-diHB) to bypass defects in the penultimate step of CoQ pathways and responses to stressors, and are dynamic, with biosynthesis, which is mediated by CoQ hydroxylase.8 these functions being tightly linked to their form, fission and 7 Treatment with 2,4-diHB improved survival and, despite persistence of proteinuria, reduced sclerotic glomeruli and Published online ahead of print. Publication date available at www.jasn.org. expression of fibrotic markers, and improved plasma albumin Correspondence: Dr. Ilse S. Daehn, Department of Medicine, Icahn School of level and renal function. Podocytes increased expression Medicine at Mount Sinai, 1468 Madison Avenue, Annenberg Building 18-72, of nephrin and synaptopodin, preserving slit morphology New York City, NY 10029. Email: [email protected] without foot process effacement. The work highlights the im- Copyright © 2020 by the American Society of Nephrology portance of diagnosing mutations in mitochondrial proteins.

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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.

13 The authors suggest the intriguing possibility that early inter- patients have lower plasma concentrations of CoQ10, and vention bypassing dysfunctional CoQ10 biosynthesis could be an where supplementation or bypassing dysfunctional CoQ10 effective and safe treatment for patients with ADCK4 mutations. biosynthesis may improve mitochondrial function, decrease The work by Widmeier et al.6 emphasizes the effect of im- oxidative stress, and slow progression. Also, as genetic testing paired electron transport in podocytes in the maintenance of becomes more prevalent and affordable, we can expect that the glomerular filtration barrier. These findings are in agree- opportunities for a “precision medicine” approach will be- ment with recent research demonstrating that the loss-of- come available for patients with nephrotic syndrome. function mutation of the complex IV assembly Unanswered questions remain about metabolic state and A: (COX10) in cells of the developing mitochondrial energetics of podocytes from mice or patients nephrons was sufficient to cause FSGS.9 COX10 is a critical with ADCK4 mutations. Future work could provide resolution complex in mitochondrial respiratory ATP production, and of the response by other glomerular cells, because dysfunc- deletion leads to mitochondrial dysfunction in podocytes. tioning podocytes likely signal to neighboring endothelial However, diverse and unexpected functions of podocyte mi- cells,14 which in this case would also harbor the ADCK4 mu- tochondria under physiologic and stress conditions continue tation, specifying reparative or pathologic responses. Because to emerge. For instance, podocyte-specificdeletionofinner mutations of mitochondrial proteins cause disease in a limited mitochondrial membrane Mpv17, involved in mito- range of organs, new approaches to better understand mi- chondrial DNA maintenance, or deletion of ABCA1,which tochondrial contributions in specific cells and tissues, in regulates the cholesterol efflux and cardiolipin content, results homeostasis and disease, is warranted. in mitochondrial dysfunction and severe glomerular disease phenotype under conditions of stress.10,11 Although these proteins do not affect the OXPHOS machinery directly, they DISCLOSURES protect podocytes against oxidative stress–induced injury. Im- portantly, when clearance of defective podocyte mitochondria Dr. Daehn has a consultancy agreement with CAMP4. is impaired, FSGS ensues, with enlarged dysfunctional mito- chondria and increased ROS.12 Mechanistic insight obtained from patients with rare forms FUNDING of monogenic disease such as ADCK4 provide an invaluable opportunity to dissect the underlying molecular mechanisms This study was supported by National Institutes of Health grant of more common disease conditions, such CKD, where the R01DK097253 (to Dr. Daehn).

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