title: Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle.
abstract: The balance between mitochondrial fission and fusion is crucial for mitochondria to perform its normal cellular functions. We hypothesized that cigarette smoke (CS) disrupts this balance and enhances mitochondrial dysfunction in the airway. In nonasthmatic human airway smooth muscle (ASM) cells, CS extract (CSE) induced mitochondrial fragmentation and damages their networked morphology in a concentration-dependent fashion, via increased expression of mitochondrial fission protein dynamin-related protein 1 (Drp1) and decreased fusion protein mitofusin (Mfn) 2. CSE effects on Drp1 vs. Mfn2 and mitochondrial network morphology involved reactive oxygen species (ROS), activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C (PKC) and proteasome pathways, as well as transcriptional regulation via factors such as NF-κB and nuclear erythroid 2-related factor 2. Inhibiting Drp1 prevented CSE effects on mitochondrial networks and ROS generation, whereas blocking Mfn2 had the opposite, detrimental effect. In ASM from asmatic patients, mitochondria exhibited substantial morphological defects at baseline and showed increased Drp1 but decreased Mfn2 expression, with exacerbating effects of CSE. Overall, these results highlight the importance of mitochondrial networks and their regulation in the context of cellular changes induced by insults such as inflammation (as in asthma) or CS. Altered mitochondrial fission/fusion proteins have a further potential to influence parameters such as ROS and cell proliferation and apoptosis relevant to airway diseases.
authors.affiliation: Division of Anesthesia Research, Dept. of Anesthesiology, 4-184 W. Joseph SMH, Mayo Clinic, Rochester, MN 55905. prakash.ys@mayo.edu.
authors.forename: Bharathi
authors.initials: B
authors.lastname: Aravamudan
authors.forename: Alexander
authors.initials: A
authors.lastname: Kiel
authors.forename: Michelle
authors.initials: M
authors.lastname: Freeman
authors.forename: Philippe
authors.initials: P
authors.lastname: Delmotte
authors.forename: Michael
authors.initials: M
authors.lastname: Thompson
authors.forename: Robert
authors.initials: R
authors.lastname: Vassallo
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004272:DNA, Mitochondrial / Q000187:drug effects*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species; D012907:Smoking / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D034281:Dynamins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; C470018:MFN2 protein, human; C110768:DNM1L protein, human
keywords: asthma; dynamin-related protein 1; lung; mitochondria; mitofusin 2; signaling