Abstract
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 Statement
AGK 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.
Abbreviations
- OD
- Organic Dust
- ODE
- Orgaic Dust Extract
- EP
- Ethyl Pyruvate
- MA
- Mitoapocynin
- LPS
- Lipopolysaccharide
- PGN
- Peptidoglycan
- PAMPs
- Pathogen Associated Molecular Patterns
- COPD
- Chronic Obstructive Pulmonary Disease
- AHR
- Airway hyperresponsiveness
- ROS
- Reactive Oxygen Species
- RNS
- Reactive Nitrogen Species
- ATP
- Adenosine Triphosphate
- OXPHOS
- Oxidative Phosphorylation
- HMGB1
- High Mobility Group Box 1
- STAT
- Signal Transducer and Activator of Transcription
- TPP
- Triphenylphosphonium
- MPTP
- 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine
- iNOS
- inducible Nitric Oxide Synthase
- NOX
- NADPH Oxidase
- MTT
- 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide
- TEM
- Transmission Electron Microscopy
- DMSO
- Dimethyl Sufoxide
- mtND1
- mitochondrial NADH dehydrogenase 1
- MFN
- Mitofusin
- OPA1
- Optic Atrophy 1
- DRP1
- Dynamin-related protein 1
- ER
- Endoplasmic Reticulum
- PINK1
- PTEN- induced kinase 1
- BNIP3
- Bcl-2 Homology 3 (BH3)-only
- MPT
- Mitochondrial Permeability Transition
- COX4i2
- Cytochrome C Oxidase subunit 4 isoform 2
- ETC
- Electron Transport Chain
- SOD2
- Superoxide Dismutase 2
- mtDAMPs
- mitochondrial Damage Associated Molecular Patters
- mtTFA
- mitochondrial Transcription Factor A
- MGC
- Multinucleated Giant Cell
- FBR
- Foreign Body Reactions
- OMM
- Outer Mitochondrial Membrane
- IMM
- Inner Mitochondrial Membrane
- IMS
- Intermembrane Space
- IL
- Interleukin
- cGAS
- cyclic GMP-AMP synthase
- TLR
- Toll-like receptor
- RAGE
- Receptor for advanced glycation end products
- VDAC
- Voltage-dependent anion channel