Heightened mitochondrial respiration in CF cells is normalised by triple CFTR modulator therapy through mechanisms involving calcium.

Autor:	Jarosz-Griffiths HH; Leeds Institute of Medical Research, University of Leeds, United Kingdom., Caley LR; Leeds Institute of Medical Research, University of Leeds, United Kingdom., Lara-Reyna S; Institute of Microbiology and Infection, University of Birmingham, United Kingdom., Savic S; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom.; Department of Clinical Immunology and Allergy, St James's University Hospital, United Kingdom., Clifton IJ; Department of Respiratory Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom., McDermott MF; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom., Peckham DG; Leeds Institute of Medical Research, University of Leeds, United Kingdom.; Department of Respiratory Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
Jazyk:	angličtina
Zdroj:	Heliyon [Heliyon] 2024 Oct 11; Vol. 10 (20), pp. e39244. Date of Electronic Publication: 2024 Oct 11 (Print Publication: 2024).
DOI:	10.1016/j.heliyon.2024.e39244
Abstrakt:	Background: Cystic fibrosis (CF) is associated with increased resting energy expenditure. However, the introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has resulted in a paradigm shift in nutritional status for many people with CF, with increase body mass index and reduction in the need for nutritional support. While these changes are likely to reflect improved clinical status and an associated downregulation of energy expenditure, they may also reflect drug-induced alterations in metabolic perturbations within CF cells. We hypothesise that some of these changes relate to normalisation of mitochondrial respiration in CF. Methods: Using wild-type (WT) and F508del/F508del CFTR human bronchial epithelial cell lines (HBE cell lines) and baby hamster kidney (BHK) cells we examined the impact of ETI on cellular metabolism. We monitored mitochondrial respiration, using Seahorse extracellular flux assays and monitored mitochondrial reactive oxygen species (mROS) and intracellular calcium levels by flow cytometry. Results: Increased mitochondrial respiration was found in HBE cell lines and BHK cells expressing CFTR F508del/F508del when assessing basal, maximal, spare respiratory capacities and ATP production, as well as increased mitochondrial ROS generated via forward electron transport. ETI significantly decreased basal, maximal, spare respiratory capacity and ATP production to WT levels or below. Calcium blocker, BAPTA-AM normalised mitochondrial respiration, suggesting a calcium-mediated mechanism. ETI decreased intracellular calcium levels in CF cells to the same extent as BAPTA-AM, highlighting the importance of calcium and chloride in mitochondrial respiration in CF. Conclusions: CF cell lines exhibit increased mitochondrial respiration, which can be downregulated by ETI therapy through mechanisms involving calcium. Competing Interests: 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. (© 2024 The Authors.)
Databáze:	MEDLINE
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