Misdiagnosis in mucopolysaccharidoses.

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Abstract

[Indexed for MEDLINE] 4. Kidney Int. 2025 Jun;107(6):1017-1036. doi: 10.1016/j.kint.2025.01.022. Epub 2025 Feb 6. Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder. Hsu SN(1), Stephen LA(2), Phadwal K(2), Dillon S(2), Carter R(3), Morton NM(3), Luijten I(3), Emelianova K(4), Amin AK(5), Macrae VE(6), Freeman TC(2), Hsu YJ(7), Staines KA(8), Farquharson C(2). Author information: (1)Division of Functional Genetics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK; Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: h720127@gmail.com. (2)Division of Functional Genetics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK. (3)Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. (4)UK Dementia Research Institute, University of Edinburgh, Edinburgh Medical School, Edinburgh, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. (5)Edinburgh Orthopaedics, Royal Infirmary of Edinburgh, Edinburgh, UK. (6)Division of Functional Genetics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK; School of Life Sciences, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, UK. (7)Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. (8)Centre for Lifelong Health, School of Applied Sciences, University of Brighton, Brighton, UK. Chronic kidney disease-mineral and bone disorder (CKD-MBD) presents with extra-skeletal calcification and renal osteodystrophy (ROD). However, the pathophysiology of ROD remains unclear. Here we examine the hypothesis that stalled mitophagy within osteocytes of CKD-MBD mouse models contributes to bone loss. RNA-seq analysis revealed an altered expression of genes associated with mitophagy and mitochondrial function in tibia of CKD-MBD mice. The expression of mitophagy regulators, p62/SQSTM1, ATG7 and LC3, was inconsistent with functional mitophagy, and in mito-QC reporter mice with ROD, there was a two- to three-fold increase in osteocyte mitolysosomes. To determine if uremic toxins were potentially responsible for these observations, treatment of cultured osteoblasts with uremic toxins revealed increased mitolysosome number and mitochondria with distorted morphology. Membrane potential and oxidative phosphorylation were also decreased, and oxygen-free radical production increased. The altered p62/SQSTM1 and LC3-II expression was consistent with impaired mitophagy machinery, and the effects of uremic toxins were reversible by rapamycin. A causal link between uremic toxins and the development of mitochondrial abnormalities and ROD was established by showing that a mitochondria-targeted antioxidant (MitoQ) and the charcoal adsorbent AST-120 were able to mitigate the uremic toxin-induced mitochondrial changes and improve bone health. Overall, our study shows that impaired clearance of damaged mitochondria may contribute to the ROD phenotype. Targeting uremic toxins, oxygen-free radical production and the mitophagy process may offer novel routes for intervention to preserve bone health in patients with CKD-MBD. This would be timely as our current armamentarium of anti-fracture medications for patients with severe CKD-MBD is limited. Copyright © 2025 International Society of Nephrology. All rights reserved. DOI: 10.1016/j.kint.2025.01.022