ETI corrector therapy suppresses mitochondrial respiration independently of CFTR mutational status.

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.