Organic Dust Exposure Induces Stress Response and Mitochondrial Dysfunction in Monocytic Cells
Exposure to airborne organic dust (OD), rich in microbial pathogen-associated molecular patterns, has been shown to induce inflammatory responses in the lung resulting in changes in airway structure and function. A common manifestation in lung inflammation is the occurrence of altered mitochondrial structure and bioenergetics, consequently regulating mitochondrial ROS (mROS) and creating a vicious cycle of mitochondrial dysfunction.The role of mitochondrial dysfunction in airway diseases such as COPD and asthma is well known. However, whether OD exposure induces mitochondrial dysfunction largely remains unknown. Therefore, in this study, we tested a hypothesis that OD exposure induces mitochondrial stress using a human monocytic cell line (THP-1). We examined the mechanisms of organic dust extract (ODE) exposure-induced mitochondrial structural and functional changes in THP-1 cells.In addition, the effect of co-exposure to ethyl pyruvate (EP), a known anti-inflammatory agent, or mitoapocynin (MA), a mitochondria targeting NOX2 inhibitor was examined. Transmission electron microscopy images showed significant changes in cellular and organelle morphology upon ODE exposure. ODE exposure with and without EP co-treatment increased the mtDNA leakage into the cytosol. Next, ODE exposure increased the PINK1 and Parkin expression, cytoplasmic cytochrome c levels and reduced mitochondrial mass and cell viability, indicating mitophagy. MA treatment was partially protective by decreasing Parkin expression, mtDNA and cytochrome c release and increasing cell viability.Competing Interest StatementAGK has an equity interest in PK Biosciences Corporation located in Ames, IA. The terms of this arrangement have been reviewed and approved by Iowa State University per its conflict of interest policies. All other authors have declared no potential conflicts of interest. AbbreviationsODOrganic DustODEOrgaic Dust ExtractEPEthyl PyruvateMAMitoapocyninLPSLipopolysaccharidePGNPeptidoglycanPAMPsPathogen Associated Molecular PatternsCOPDChronic Obstructive Pulmonary DiseaseAHRAirway hyperresponsivenessROSReactive Oxygen SpeciesRNSReactive Nitrogen SpeciesATPAdenosine TriphosphateOXPHOSOxidative PhosphorylationHMGB1High Mobility Group Box 1STATSignal Transducer and Activator of TranscriptionTPPTriphenylphosphoniumMPTP1-Methyl-4-Phenyl-1,2,3,6-TetrahydropyridineiNOSinducible Nitric Oxide SynthaseNOXNADPH OxidaseMTT3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromideTEMTransmission Electron MicroscopyDMSODimethyl SufoxidemtND1mitochondrial NADH dehydrogenase 1MFNMitofusinOPA1Optic Atrophy 1DRP1Dynamin-related protein 1EREndoplasmic ReticulumPINK1PTEN- induced kinase 1BNIP3Bcl-2 Homology 3 (BH3)-onlyMPTMitochondrial Permeability TransitionCOX4i2Cytochrome C Oxidase subunit 4 isoform 2ETCElectron Transport ChainSOD2Superoxide Dismutase 2mtDAMPsmitochondrial Damage Associated Molecular PattersmtTFAmitochondrial Transcription Factor AMGCMultinucleated Giant CellFBRForeign Body ReactionsOMMOuter Mitochondrial MembraneIMMInner Mitochondrial MembraneIMSIntermembrane SpaceILInterleukincGAScyclic GMP-AMP synthaseTLRToll-like receptorRAGEReceptor for advanced glycation end productsVDACVoltage-dependent anion channelView Full Text