Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb–deficient Bartter syndrome mice
- 1Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
- 2Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
- 3Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
Abstract
The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle’s loop (TAL). By studying Clc-k2–KO (mouse ortholog of ClC-Kb–KO [Clc-k2–/–]) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2–/– and WT mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results reveal impairments in cell proliferation, S-to-G2/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2–/– TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 (Wnk4) mutation in Clc-k2–/– mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor γ coactivator-1α, a master regulator of mitochondrial biogenesis, in Clc-k2–/– mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a therapeutic approach for BS.
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BibTeX
@article{hsieh2026mitochondrial,
title = {{Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb–deficient Bartter syndrome mice}},
author = {Chiao-Hui Hsieh and Yu-Jen Chen and Chih-Chien Sung and Emily Morrison and Chou-Long Huang and Chih-Jen Cheng},
journal = {JCI Insight},
year = {2026},
month = aug,
doi = {10.1172/jci.insight.201067},
url = {https://doi.org/10.1172/jci.insight.201067},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb–deficient Bartter syndrome mice
AU - Chiao-Hui Hsieh
AU - Yu-Jen Chen
AU - Chih-Chien Sung
AU - Emily Morrison
AU - Chou-Long Huang
AU - Chih-Jen Cheng
PY - 2026
DA - 2026/08/20
JO - JCI Insight
DO - 10.1172/jci.insight.201067
UR - https://doi.org/10.1172/jci.insight.201067
AB - The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased salt reabsorption in the thick ascending limb of Henle’s loop (TAL). By studying Clc-k2–KO (mouse ortholog of ClC-Kb–KO [Clc-k2–/–]) mice, we recently uncovered an additional mechanism in which loss of Clc-k2 induces TAL hypoplasia in neonatal kidneys, exacerbating BS severity. Here, we further investigated this mechanism. TALs and distal convoluted tubules (DCTs) isolated from Clc-k2–/– and WT mice were used for transcriptome, proteomics, cell cycle, and proliferation assays. Mitochondrial morphology and function were studied using electron microscopy and mitochondrial respiration assays. Our results reveal impairments in cell proliferation, S-to-G2/M cell cycle transition, mitochondrial biogenesis, oxidative phosphorylation, glycolysis, and fatty acid oxidation in Clc-k2–/– TALs and DCTs. Increasing transport function by introducing a gain-of-function with-no-lysine kinase 4 (Wnk4) mutation in Clc-k2–/– mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor γ coactivator-1α, a master regulator of mitochondrial biogenesis, in Clc-k2–/– mice also alleviated mitochondrial dysfunction and phenotype. These findings support the hypothesis that mitochondrial hypofunction, resulting from decreased transport function, contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a therapeutic approach for BS.
SN - 2379-3708
ER -