title: Mitochondrial complex III-generated oxidants activate ASK1 and JNK to induce alveolar epithelial cell death following exposure to particulate matter air pollution.
abstract: We have previously reported that airborne particulate matter air pollution (PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells through a pathway that requires the mitochondrial generation of reactive oxygen species (ROS) and the activation of p53. We sought to examine the source of mitochondrial oxidant production and the molecular links between ROS generation and the activation of p53 in response to PM exposure. Using a mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking mitochondrial DNA (rho0 cells) and cells stably expressing a small hairpin RNA directed against the Rieske iron-sulfur protein, we show that site III of the mitochondrial electron transport chain is primarily responsible for fine PM (PM2.5)-induced oxidant production. In alveolar epithelial cells, the overexpression of SOD1 prevented the PM2.5-induced ROS generation from the mitochondria and prevented cell death. Infection of mice with an adenovirus encoding SOD1 prevented the PM2.5-induced death of alveolar epithelial cells and the associated increase in alveolar-capillary permeability. Treatment with PM2.5 resulted in the ROS-mediated activation of the oxidant-sensitive kinase ASK1 and its downstream kinase JNK. Murine embryonic fibroblasts from ASK1 knock-out mice, alveolar epithelial cells transfected with dominant negative constructs against ASK1, and pharmacologic inhibition of JNK with SP600125 (25 microM) prevented the PM2.5-induced phosphorylation of p53 and cell death. We conclude that particulate matter air pollution induces the generation of ROS primarily from site III of the mitochondrial electron transport chain and that these ROS activate the intrinsic apoptotic pathway through ASK1, JNK, and p53.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Christina M
authors.initials: CM
authors.lastname: Baker
authors.forename: Zach
authors.initials: Z
authors.lastname: Burgess
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Andrea
authors.initials: A
authors.lastname: De Vizcaya-Ruiz
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ridge
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
mesh_terms: D000393:Air Pollutants / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D014450:Electron Transport Complex III / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000393:Air Pollutants; D016877:Oxidants; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D014450:Electron Transport Complex III