Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice

Chiao-Hui Hsieh; Yu-Jen Chen; Chih-Chien Sung; Emily Morrison; Chou-Long Huang; Chih-Jen Cheng

doi:10.1172/jci.insight.201067

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Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice

Journal article

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Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice

Chiao-Hui Hsieh, Yu-Jen Chen, Chih-Chien Sung, Emily Morrison, Chou-Long Huang and Chih-Jen Cheng

JCI insight

08/20/2026

DOI: 10.1172/jci.insight.201067

PMID: 42623150

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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 (mouse ortholog of ClC-Kb)-knockout (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 wild-type 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 revealed 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 mutation in Clc-k2-/- mice restored these metabolic and proliferative impairments and improved phenotype. Transgenic expression of peroxisome proliferator-activated receptor gamma 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 potential therapeutic approach for BS.

Cell Biology

Nephrology

Cell Cycle

Mitochondria

Epithelial transport of ions and water

Details

Title: Subtitle: Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice
Creators: Chiao-Hui Hsieh - University of Iowa, Internal Medicine
Yu-Jen Chen - University of Iowa
Chih-Chien Sung - National Defense Medical Center
Emily Morrison - University of Iowa
Chou-Long Huang - University of Iowa
Chih-Jen Cheng - University of Iowa, Nephrology
Resource Type: Journal article
Publication Details: JCI insight
DOI: 10.1172/jci.insight.201067
PMID: 42623150
NLM abbreviation: JCI Insight
ISSN: 2379-3708
eISSN: 2379-3708
Publisher: American Society for Clinical Investigation
Language: English
Electronic publication date: 08/20/2026
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9985219319702771

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