Abstract
Endoplasmic Reticulum-Mitochondrion Disconnection Promotes Epigenetic Rewiring and Cystogenesis in PKD: FR-OR051
Journal of the American Society of Nephrology, Vol.36(10S)
10/2025
DOI: 10.1681/ASN.2025tntsy6j2
Abstract
Background:
Mutations in PKD1/2 cause ADPKD with mitochondrial dysfunction, metabolic reprogramming, widespread transcriptional and epigenetic changes. The pathogenesis remains elusive. Metabolic reprogramming with upregulation of asparagine synthetase (ASNS) is important. ER-localized PC2 mediates K+-Ca2+ exchange to facilitate ER Ca2+ release contributing to anti-cystogenesis. Expression of TricB, an ER-resident K+ channel, restores ER Ca2+ release and mitigates cystogenesis in Pkd2-deficiency. ER and mitochondria are in proximity forming inter-organelle structures called mitochondria-associated ER membranes (MAMs). MAMs allow inter-organelle exchange of lipids, Ca2+ and signaling. We examined the role of ER-mitochondria connection in ADPKD.
Methods:
Transmission, scanning electron microscopy, mitochondrial function, regulatory gene expression, and epigenetic analyses were studied in Pkd1- and Pkd2-cKO mice at pre-cystic (4 weeks) and cystic (16 weeks) stages.
Results:
Abnormal mitochondrial morphology and ER-mitochondria connection was observed in Pkd1/2-cKO by TEM and SEM, and by proximity ligation assay. Changes seen in pre-cystic stage with no progression to cystic stage. The defects correlated with reduced oxygen consumption, altered mitochondrial membrane potential and Ca2+ uptake indicative of mitochondrial dysfunction. The expression of genes modulating mitochondrial biogenesis, dynamics, and function were altered. We also found increased histone acetylation at loci including cMyc and Cdk7, a key metabolic reprogramming kinase. We identified enhancers of Cdk7 and showed that enhancer histone acetylation upregulated Cdk7. DNA methylation analysis revealed pathways including mitochondria phosphatase Ppm1K and transcription factor Zbtb1, linking ER-mitochondria stress to epigenetic shifts underlying metabolic reprogramming and ASNS upregulation. Above changes were reversed by transgenic TricB expression or pharmacological activators of MAM function.
Conclusion:
ER-resident PCs is important for mitochondria health. PC-mediated ER Ca2+ release defects cause an initial mitochondrial defect. Mitochondria-led epigenetic rewiring contributes to widespread genetic changes for cell proliferative and metabolic events, amplifying cystogenesis. Correcting ER-mitochondria disconnection may be an effective treatment for ADPKD.
Details
- Title: Subtitle
- Endoplasmic Reticulum-Mitochondrion Disconnection Promotes Epigenetic Rewiring and Cystogenesis in PKD: FR-OR051
- Creators
- Biswajit Padhy - University of IowaJian Xie - University of IowaDanish Idrees - University of IowaChih-Jen Cheng - University of Iowa, NephrologyChou-Long Huang - University of Iowa, Nephrology
- Resource Type
- Abstract
- Publication Details
- Journal of the American Society of Nephrology, Vol.36(10S)
- DOI
- 10.1681/ASN.2025tntsy6j2
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Publisher
- American Society of Nephrology
- Language
- English
- Date published
- 10/2025
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9985019045202771
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