PXD069389-1

PXD069389 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice
Description	The pathogenesis of Bartter syndrome (BS) has long been attributed to decreased NaCl 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 transport function induces TAL hypoplasia, exacerbating the severity of BS. 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, and 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 activity by introducing a gain-of-function with-no-lysine 4 (Wnk4) mutation in Clc-k2-/- mice restored all the abovementioned impairments and improved medulla maturation and phenotype. Transgenic overexpression of Pgc1α, a master activator 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 activity contributes to cell cycle arrest and tubular hypoplasia in BS. Targeting mitochondria early in life could be a potential therapeutic approach for BS.
HostingRepository	PRIDE
AnnounceDate	2026-07-10
AnnouncementXML	Submission_2026-07-09_22:57:52.708.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chiao Hui Hsieh
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-13 04:03:00	ID requested
⏵ 1	2026-07-09 22:57:53	announced

Dataset with its publication pending

submitter keyword: metabolism, Clc-k2, mitochondria, cell cycle,Bartter syndrome type 3

Chih-Jen Cheng
contact affiliation	Division of Nephrology, Department of Medicine Carver College of Medicine, University of Iowa
contact email	chih-jen-cheng@uiowa.edu
lab head
Chiao Hui Hsieh
contact affiliation	University of iowa
contact email	chiao-hui-hsieh@uiowa.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069389
     1. Label: PRIDE project
     2. Name: Mitochondrial dysfunction underlies cell cycle arrest and tubular hypoplasia in ClC-Kb-deficient Bartter syndrome mice