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Abstract: TH-OR64

Role of ER-Mitochondria Connection in the Pathogenesis of ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Padhy, Biswajit, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
  • Xie, Jian, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
  • Huang, Chou-Long, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States

Group or Team Name

  • Huang Lab.

Mutations in PKD1 and PKD2 gene cause ADPKD. One hypothesis states that ADPKD is a ciliopathy. We have recently demonstrated that ER-localized PC2 is also important in anti-cystogenesis via K+-Ca2+exchange for ER Ca2+ release. Metabolic reprogramming and mitochondrial dysfunction are important in pathogenesis of ADPKD. Mitochondrial (Mito) translocation of the C-terminal tail of PC1 (CTT) is believed important. How PC2 regulates Mito function is unknown. 3 potential mechanisms underlie regulation of Mito by PC2-mediated ER Ca2+ release: direct ER-Mito Ca2+ transfer at mitochondria-associated ER membranes (MAMs) to regulate TCA enzyme, and cytosolic Ca2+ regulation of PGC1α (via CaMKII) and PPARα (via myc and miR17), two master regulators of Mito biogenesis.


TricB, an ER-restricted K+ channel mediates K+-Ca2+ exchange for Ca2+ release as an experimental tool for role of ER-localized PC2. Oxygen consumption rate (OCR) for Mito function and transmission EM (TEM) for Mito morphology.


Mito DNA mass, PPARα, PGC1α, mitofusin-2 were downregulated while myc and miR-17 were upregulated in both Pkd1- and Pkd2-cKO kidneys. OCR decreased in proximal tubules isolated from both Pkd1- and Pkd2-cKO kidneys. TEM revealed ER in close contact with Mito forming MAMs. About 25% ER membrane and 60% Mito membrane form MAMs. Mito morphology (area, cristae density, roundness, etc) were altered in Pkd2-cKO kidneys. MAM distance was increased in Pkd2-cKO, indicating reduced ER-Mito contact. In many parameters measured, changes occurred in pre-cystic as well cystic stage. In all above, the changes by cKO were reversed at least partially by transgenic expression of TricB, indicating PC2-dependent ER Ca2+ release is important. To further demonstrate convergence of PC1 and PC2 function in ER, transgenic TricB expression reversed cystogenesis in Pkd1-cKO mice. Interestingly, PC1-CTT translocation to Mito decreased in Pkd2-cKO, which was reversed by TricB expression.


Both PC1 and PC2 deficiency result in mitochondrial dysfunction. TricB is not in cilia nor Mito; complementation of the deficiency by TricB supports an important role for ER Ca2+ homeostasis. ER-mitochondria connection is a downstream effector for PC1 and PC2 convergence and plays an important role in anti-cystogenesis of PCs.


  • NIDDK Support