Dysfunction of mitochondria Ca2+ uptake in cystic fibrosis airway epithelial cells.
In the genetic disease cystic fibrosis (CF), the most common mutation F508del promotes the endoplasmic reticulum (ER) retention of misfolded CF proteins. Furthermore, in homozygous F508del-CFTR airway epithelial cells, the histamine Ca(2+) mobilization is abnormally increased. Because the uptake of Ca(2+) by mitochondria during Ca(2+) influx or Ca(2+) release from ER stores may be crucial for maintaining a normal Ca(2+) homeostasis, we compared the mitochondria morphology and distribution by transmission electron microscopy technique and the mitochondria membrane potential variation (DeltaPsi(mit)) using a fluorescent probe (TMRE) on human CF (CF-KM4) and non-CF (MM39) tracheal serous gland cell lines. Confocal imaging of Rhod-2-AM-loaded or of the mitochondrial targeted cameleon 4mtD3cpv-transfected human CF and non-CF cells, were used to examine the ability of mitochondria to sequester intracellular Ca(2+). The present study reveals that (i) the mitochondria network is fragmented in F508del-CFTR cells, (ii) the DeltaPsi(mit) of CF mitochondria is depolarized compared non-CF mitochondria, and (iii) the CF mitochondria Ca(2+) uptake is reduced compared non-CF cells. We propose that these defects in airway epithelial F508del-CFTR cells are the consequence of mitochondrial membrane depolarization leading to a deficient mitochondrial Ca(2+) uptake.
Antigny
Fabrice
F
Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS, 40 Avenue du recteur pineau, Poitiers F-86022, France.
Girardin
Nathalie
N
Raveau
Dorothée
D
Frieden
Maud
M
Becq
Frédéric
F
Vandebrouck
Clarisse
C
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D012137:Respiratory System / Q000473:pathology*
D002118:Calcium