Preprint
Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity
bioRxiv
Cold Spring Harbor Laboratory
07/10/2026
DOI: 10.64898/2026.07.09.737340
PMID: 42465480
Abstract
Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear. We show that QKI expression is reduced in human COPD lungs and that alveolar type 2 epithelial (AT2) cell QKI protein levels correlate strongly with spirometric indices and diffusing capacity (DL
). Lung epithelium-specific QKI knockout mice (QKI
) developed spontaneous airspace enlargement with emphysema-like mechanics, and QKI-deficient AT2 cells showed impaired spheroid colony formation and increased apoptosis. Integrated transcriptomic and proteomic analyses of primary AT2 cells revealed a selective reduction in functional mitochondrial (respiratory-chain and metabolic) protein abundance despite relatively preserved transcript levels, consistent with mitochondrial transcriptome-proteome discordance. QKI loss increased mtDNA abundance and TOMM20 staining but decreased ATP5A, indicating accumulation of structurally increased but functionally dysfunctional mitochondria. In human epithelial cells, CRISPR-mediated QKI deficiency reduced oxidative respiration, increased glycolytic reliance, elevated mitochondrial ROS and membrane potential, and increased apoptosis; these phenotypes were partially rescued by QKI re-expression. These findings identify epithelial QKI as a regulator of mitochondrial integrity and stress tolerance in COPD.
Details
- Title: Subtitle
- Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity
- Creators
- Kiyoshi Uemasu - University of PittsburghKazuya Tanimura - University of PittsburghAtsushi Miyamoto - University of PittsburghKoichi Hasegawa - University of North Carolina at Chapel HillZachary Lane - University of PittsburghReika Nyunoya - University of PittsburghHaruka Uemasu - University of PittsburghBrett A Kaufman - University of PittsburghCorrine R Kliment - University of PittsburghDivay Chandra - University of PittsburghFrank Sciurba - University of PittsburghCharles Dela CruzPrithu Sundd - Versiti Blood Center of WisconsinJonathan K Alder - University of PittsburghJian Hu - The University of Texas MD Anderson Cancer CenterToru Nyunoya - University of Pittsburgh
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.64898/2026.07.09.737340
- PMID
- 42465480
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory; United States
- Grant note
- I01 BX006096 / BLRD VA R01 HL149719 / NHLBI NIH HHS
- Language
- English
- Date posted
- 07/10/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217040302771
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