Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder

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Hsu, S-N, Stephen, LA, Phadwal, K, Dillon, S, Carter, R, Morton, NM ORCID: https://orcid.org/0000-0001-8218-8462, Luijten, I, Emelianova, K, Amin, AK, Macrae, VE, Freeman, TC, Hsu, Y-J, Staines, KA and Farquharson, C, 2025. Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder. Kidney International, 107 (6), pp. 1017-1036. ISSN 0085-2538

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Official URL: https://doi.org/10.1016/j.kint.2025.01.022

Abstract

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.

Item Type:	Journal article
Publication Title:	Kidney International
Creators:	Hsu, S.-N., Stephen, L.A., Phadwal, K., Dillon, S., Carter, R., Morton, N.M., Luijten, I., Emelianova, K., Amin, A.K., Macrae, V.E., Freeman, T.C., Hsu, Y.-J., Staines, K.A. and Farquharson, C.
Publisher:	Elsevier
Date:	June 2025
Volume:	107
Number:	6
ISSN:	0085-2538
Identifiers:	Number Type 10.1016/j.kint.2025.01.022 DOI S0085253825000857 Publisher Item Identifier 2465167 Other
Rights:	© 2025 International Society of Nephrology. Published by Elsevier Inc. Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	08 Jul 2025 22:54
Last Modified:	08 Jul 2025 22:54
URI:	https://irep.ntu.ac.uk/id/eprint/53909