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Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells.

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.

SUBMITTER: Wang HT

PROVIDER: S-EPMC5642564 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells.

Wang Hsiang-Tsui HT Lin Jing-Heng JH Yang Chun-Hsiang CH Haung Chun-Hao CH Weng Ching-Wen CW Maan-Yuh Lin Anya A Lo Yu-Li YL Chen Wei-Shen WS Tang Moon-Shong MS

Oncotarget 20170731 41

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 ...[more]

PMID: 29050289

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Project description:Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related proteins were assessed in transforming growth factor beta 1 (TGF-β1)-activated CF, whereas the role of mitochondrial fission during this process was also elucidated, as were the underlying mechanisms. The interaction between mitochondrial fission and mitophagy, the main defense mechanism against mitochondrial impairment, was also explored. The results showed that the mitochondria in TGF-β1-treated CF were noticeably more fragmented than those of controls. The expression of several mitochondrial fission-related proteins was markedly upregulated, and the levels of fusion-related proteins were also altered, but to a lesser extent. Inhibiting mitochondrial fission resulted in a marked attenuation of TGF-β1-induced CF activation. The TGF-β1-induced increase in glycolysis was greatly suppressed in the presence of a mitochondrial inhibitor, whereas a glycolysis-specific antagonist exerted little additional antifibrotic effects. TGF-β1 treatment increased cellular levels of reactive oxygen species (ROS) and triggered mitophagy, but this effect was reversed following the application of ROS scavengers. For the signals mediating mitophagy, the expression of Pink1, but not Bnip3l/Nix or Fundc1, exhibited the most significant changes, which could be counteracted by treatment with a mitochondrial fission inhibitor. Pink1 knockdown suppressed CF activation and mitochondrial fission, which was accompanied by increased CF apoptosis. In conclusion, mitochondrial fission resulted in increased glycolysis and played a crucial role in CF activation. Moreover, mitochondrial fission promoted reactive oxygen species (ROS) production, leading to mitophagy and the consequent degradation of the impaired mitochondria, thus promoting CF survival and maintaining their activation.

Dataset Information

Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells.

Publications

Acrolein induces mtDNA damages, mitochondrial fission and mitophagy in human lung cells.

Similar Datasets

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