Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral
Shun-Neng Hsu1, Louise A Stephen2, Kanchan Phadwal2
1Division 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.
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.
Insights
Impaired mitophagy in osteocytes contributes to bone loss in chronic kidney disease-mineral and bone disorder (CKD-MBD). Targeting uremic toxins and oxidative stress may preserve bone health in CKD-MBD patients.
Area of Science:
- Nephrology
- Bone Biology
- Mitochondrial Biology
Background:
- Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by extra-skeletal calcification and renal osteodystrophy (ROD).
- The precise pathophysiology of ROD and associated bone loss in CKD-MBD remains incompletely understood.
- Osteocyte dysfunction is increasingly recognized as a contributor to bone abnormalities in CKD.
Purpose of the Study:
- To investigate the hypothesis that impaired mitophagy in osteocytes contributes to bone loss in CKD-MBD.
- To explore the role of uremic toxins in inducing mitochondrial dysfunction and mitophagy defects in osteoblasts.
- To identify potential therapeutic targets for preserving bone health in CKD-MBD.
Main Methods:
- RNA-sequencing of tibia from CKD-MBD mouse models to analyze gene expression related to mitophagy and mitochondrial function.
- Utilized mito-QC reporter mice to quantify osteocyte mitolysosomes and assess mitophagy flux.
- Treated cultured osteoblasts with uremic toxins to evaluate mitochondrial morphology, membrane potential, oxidative phosphorylation, and reactive oxygen species (ROS) production.
- Administered rapamycin, a mitochondria-targeted antioxidant (MitoQ), and AST-120 to assess their effects on uremic toxin-induced changes and bone health.
Main Results:
- CKD-MBD mice exhibited altered gene expression in mitophagy and mitochondrial pathways.
- Increased osteocyte mitolysosomes in ROD mice and cultured osteoblasts treated with uremic toxins indicated stalled mitophagy.
- Uremic toxins impaired mitochondrial function, increased ROS production, and altered mitophagy markers (p62/SQSTM1, LC3-II).
- Rapamycin, MitoQ, and AST-120 mitigated uremic toxin-induced mitochondrial damage and improved bone health markers.
Conclusions:
- Impaired clearance of damaged mitochondria via mitophagy is a significant contributor to the renal osteodystrophy phenotype in CKD-MBD.
- Uremic toxins play a causal role in mitochondrial dysfunction and bone loss in CKD-MBD.
- Targeting uremic toxins, ROS production, and the mitophagy pathway presents promising therapeutic strategies for bone protection in CKD-MBD.
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