Academic Journal
ETI corrector therapy suppresses mitochondrial respiration independently of CFTR mutational status.
| Τίτλος: | ETI corrector therapy suppresses mitochondrial respiration independently of CFTR mutational status. |
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| Συγγραφείς: | Jha A; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA., Mishra SK; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA., Zhang Y; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA., Bharathi S; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA., Goetzman ES; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA. Electronic address: Eric.goetzman@chp.edu. |
| Πηγή: | Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2026 Jul 02; Vol. 820, pp. 153848. Date of Electronic Publication: 2026 Apr 27. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE |
| Imprint Name(s): | Publication: <2002- >: San Diego, CA : Elsevier Original Publication: New York, Academic Press. |
| Ιατρικοί όροι (MeSH): | Cystic Fibrosis Transmembrane Conductance Regulator*/genetics , Cystic Fibrosis Transmembrane Conductance Regulator*/metabolism , Mitochondria*/metabolism , Mitochondria*/drug effects , Aminophenols*/pharmacology , Quinolones*/pharmacology , Pyrazoles*/pharmacology , Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/genetics , Cystic Fibrosis*/metabolism , Benzodioxoles*/pharmacology , Indoles*/pharmacology , Pyrrolidines*/pharmacology , Oximes*/pharmacology , Pyridines*/pharmacology, Cell Respiration/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Humans ; Rats ; Mutation ; Drug Combinations ; Cell Line ; Quinolines |
| Περίληψη: | The relationship between CFTR mutational status and cellular energy metabolism remains unresolved. Using continuous long-term respirometry via the Resipher platform, we demonstrate that the Class II CFTR misfolding mutations ΔF508, G85E, and P67L all significantly increase cellular respiration in isogenic Fisher rat thyroid (FRT) and human bronchial epithelial (HBE) cells, consistent with the constitutive energy demands of misfolded-protein quality control. In contrast, Class I truncating mutations (G542X, W1282X), which produce no misfolded protein and no functional ion channels, reduced cellular respiration below wildtype levels. ΔF508-expressing HBE cells also exhibited impaired metabolic flexibility under culture conditions modeling either hypoglycemia or hyperglycemia. Strikingly, treatment of HBE cells with elexacaftor/tezacaftor/ivacaftor (ETI) significantly suppressed mitochondrial respiration to a comparable degree in both ΔF508 and wildtype HBE cells across all media glucose concentrations tested, establishing a CFTR-independent metabolic effect of the drugs. Despite reduced mitochondrial respiration, intracellular ATP was maintained under ETI treatment, paralleled by significantly increased lactate secretion, indicating a compensatory Warburg-like shift toward glycolytic ATP production. These findings have potential implications for the metabolic comorbidities increasingly observed in CF patients in the ETI era. (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Grant Information: | R01 DK068196 United States DK NIDDK NIH HHS; R01 HD103602 United States HD NICHD NIH HHS |
| Contributed Indexing: | Keywords: Cellular respiration; Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Elexacaftor; Ivacaftor; Tezacaftor |
| Substance Nomenclature: | 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) 0 (Aminophenols) 0 (Quinolones) 0 (Pyrazoles) 0 (Benzodioxoles) 0 (Indoles) 0 (Drug Combinations) 0 (elexacaftor, ivacaftor, tezacaftor drug combination) 0 (Pyrrolidines) 0 (Oximes) 0 (CFTR protein, human) 8L70Q75FXE (Adenosine Triphosphate) 0 (Pyridines) 0 (Quinolines) |
| Entry Date(s): | Date Created: 20260501 Date Completed: 20260716 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| DOI: | 10.1016/j.bbrc.2026.153848 |
| PMID: | 42066560 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2104 |
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| DOI: | 10.1016/j.bbrc.2026.153848 |