Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma.
Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling.
Trian
Thomas
T
Universite Bordeaux 2, Laboratoire de Physiologie Cellulaire Respiratoire, F-33076 Bordeaux, France.
Benard
Giovanni
G
Begueret
Hugues
H
Rossignol
Rodrigue
R
Girodet
Pierre-Olivier
PO
Ghosh
Debajyoti
D
Ousova
Olga
O
Vernejoux
Jean-Marc
JM
Marthan
Roger
R
Tunon-de-Lara
José-Manuel
JM
Berger
Patrick
P
D000328:Adult; D001249:Asthma / Q000378:metabolism / Q000473:pathology*; D001980:Bronchi / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009130:Muscle, Smooth / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D051266:Nuclear Respiratory Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D002118:Calcium