Abstract
Acrolein (Acr), a highly reactive unsaturated aldehyde, can cause various lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We have found that Acr can damage not only genomic DNA but also DNA repair proteins causing repair dysfunction and enhancing cells’ mutational susceptibility. While these effects may account for Acr lung carcinogenicity, the mechanisms by which Acr induces lung diseases other than cancer are unclear. In this study, we found that Acr induces damages in mitochondrial DNA (mtDNA), inhibits mitochondrial bioenergetics, and alters mtDNA copy number in human lung epithelial cells and fibroblasts. Furthermore, Acr induces mitochondrial fission which is followed by autophagy/ mitophagy and Acr-induced DNA damages can trigger apoptosis. However, the autophagy/ mitophagy process does not change the level of Acr-induced mtDNA damages and apoptosis. We propose that Acr-induced mtDNA damages trigger loss of mtDNA via mitochondrial fission and mitophagy. These processes and mitochondria dysfunction induced by Acr are causes that lead to lung diseases.
Highlights
Acrolein (Acr), a ubiquitous environmental pollutant, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes [1,2,3,4]
We show that Acr induces many facets of mitochondrial injuries such as mitochondrial DNA (mtDNA) damages, as well as reductions of mtDNA copy number, mitochondrial RNA transcripts, cellular ATP levels, mitochondrial membrane potential and mitochondrial respiration
Since aerodigestive organs are the major targets of Acr, and Acr induces asthma, chronic obstructive pulmonary disease (COPD), and lung cancer, we used human lung cells including the epithelial adenoacarcinoma A549 cells and MRC-5 normal lung fibroblasts to dissect the mechanisms underlying Acrinduced cytotoxicity
Summary
Acrolein (Acr), a ubiquitous environmental pollutant, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes [1,2,3,4]. Acr can be produced endogenously through lipid peroxidation, resulting from free radical damage to polyunsaturated fatty acids [4]. Acr is a strong electrophile and can readily react with nucleophilic reactive groups of biomolecules, including DNA base guanosine yielding mutagenic cyclic propanodeoxyguanosine (PdG) adducts [4]. Our previous studies have shown that Acr-induced PdG adducts induce G to A transitions and G to T transversions [6,7,8,9,10]. Acr reacts with cysteine, histidine and lysine residues of proteins, resulting in inactivation of proteins [4]. We found that Acr impairs DNA repair function through modifications with repair proteins and further enhances cells’ susceptibility to DNA damage-induced mutagenesis [6,7,8,9]
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