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Objective <p>To determine how nicotine exposure in vitro and cigarette smoke (CS) exposure in vivo, together with MYST1 silencing, regulate mitophagy-associated changes and contribute to bronchial epithelial dysfunction and COPD-like pathology.</p> Methods and results <p>Human 16HBE bronchial epithelial cells were treated with nicotine (0.1 or 1 µM) and/or transfected with siRNA targeting MYST1. Mitophagy-associated markers (LC3, PINK1, BNIP3) were assessed by Western blot and immunofluorescence. Mitochondrial ultrastructure and membrane potential were evaluated by transmission electron microscopy and JC-1 staining, respectively. Apoptosis was measured by flow cytometry, and cytokines (IL-2, IL-6, TNF-α, IL-10) were quantified by ELISA. MYST1 silencing increased mitophagy-associated markers and reduced mitochondrial membrane potential. Nicotine induced a dose-dependent increase in mitophagy-associated markers and mitochondrial fragmentation. Nicotine exposure and MYST1 silencing decreased proliferation, increased apoptosis, and shifted cytokine profiles toward a pro-inflammatory pattern. RT-qPCR and ChIP-qPCR showed that MYST1 silencing upregulated PINK1 transcription and was associated with increased H4K16ac enrichment at the PINK1 promoter despite reduced global H4K16ac. In vivo, a CS-induced mouse model was established, and MYST1 was silenced by intratracheal AAV9-shRNA delivery. CS exposure induced emphysema-like injury with increased mean linear intercept (MLI), enhanced α-SMA staining, and reduced MYST1 expression, which were further aggravated by MYST1 silencing.</p> Conclusions <p>Nicotine and MYST1 loss promote mitophagy-associated alterations, epithelial injury, and inflammation, and a MYST1/H4K16ac-related pathway may contribute to smoke-associated COPD-like pathology.</p>

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Nicotine-induced mitophagy in bronchial epithelial cells and MYST1 downregulation in cigarette smoke–exposed lungs: potential mechanisms of COPD progression

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Kai Liu,
  • Dongchuan Xu,
  • Jie Zhao,
  • Rubing Mo,
  • Mei Lin,
  • Chanyi He,
  • Qi Lin,
  • Tian Xie,
  • Quanni Li,
  • Yipeng Ding

摘要

Objective

To determine how nicotine exposure in vitro and cigarette smoke (CS) exposure in vivo, together with MYST1 silencing, regulate mitophagy-associated changes and contribute to bronchial epithelial dysfunction and COPD-like pathology.

Methods and results

Human 16HBE bronchial epithelial cells were treated with nicotine (0.1 or 1 µM) and/or transfected with siRNA targeting MYST1. Mitophagy-associated markers (LC3, PINK1, BNIP3) were assessed by Western blot and immunofluorescence. Mitochondrial ultrastructure and membrane potential were evaluated by transmission electron microscopy and JC-1 staining, respectively. Apoptosis was measured by flow cytometry, and cytokines (IL-2, IL-6, TNF-α, IL-10) were quantified by ELISA. MYST1 silencing increased mitophagy-associated markers and reduced mitochondrial membrane potential. Nicotine induced a dose-dependent increase in mitophagy-associated markers and mitochondrial fragmentation. Nicotine exposure and MYST1 silencing decreased proliferation, increased apoptosis, and shifted cytokine profiles toward a pro-inflammatory pattern. RT-qPCR and ChIP-qPCR showed that MYST1 silencing upregulated PINK1 transcription and was associated with increased H4K16ac enrichment at the PINK1 promoter despite reduced global H4K16ac. In vivo, a CS-induced mouse model was established, and MYST1 was silenced by intratracheal AAV9-shRNA delivery. CS exposure induced emphysema-like injury with increased mean linear intercept (MLI), enhanced α-SMA staining, and reduced MYST1 expression, which were further aggravated by MYST1 silencing.

Conclusions

Nicotine and MYST1 loss promote mitophagy-associated alterations, epithelial injury, and inflammation, and a MYST1/H4K16ac-related pathway may contribute to smoke-associated COPD-like pathology.