4.6 Article

Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD

期刊

CELLS
卷 11, 期 3, 页码 -

出版社

MDPI
DOI: 10.3390/cells11030369

关键词

cigarette smoke; COPD; mitochondria; cell-free DNA; oxidative stress; senescence; necroptosis; extracellular vesicles

资金

  1. Vascular Medicine Institute Postdoctoral Award (2020)
  2. Flight Attendant's Medical Research Institute (FAMRI)
  3. NIH NHLBI [P50HL084948]

向作者/读者索取更多资源

This study measured the levels of cf-mtDNA and cf-nDNA in the plasma of COPD patients and the serum of mice with CS-induced emphysema and found increased levels of cf-mtDNA in both. In cell culture, exposure to CSE resulted in decreased mitochondrial membrane potential, increased oxidative stress, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles. These findings suggest that cf-mtDNA could serve as a marker of mitochondrial stress in response to CS exposure and COPD pathology.
Cigarette smoke (CS) is the most common risk factor for chronic obstructive pulmonary disease (COPD). The present study aimed to elucidate whether mtDNA is released upon CS exposure and is detected in the plasma of former smokers affected by COPD as a possible consequence of airway damage. We measured cell-free mtDNA (cf-mtDNA) and nuclear DNA (cf-nDNA) in COPD patient plasma and mouse serum with CS-induced emphysema. The plasma of patients with COPD and serum of mice with CS-induced emphysema showed increased cf-mtDNA levels. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased oxidative stress, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles (EVs). Mitochondrial DNA release into EVs occurred concomitantly with increased expression of markers that associate with DNA damage responses, including DNase III, DNA-sensing receptors (cGAS and NLRP3), proinflammatory cytokines (IL-1 beta, IL-6, IL-8, IL-18, and CXCL2), and markers of senescence (p16 and p21); the majority of the responses are also triggered by cytosolic DNA delivery in vitro. Exposure to a lethal CSE dose preferentially induced mtDNA and nDNA release in the cell debris. Collectively, the results of this study associate markers of mitochondrial stress, inflammation, and senescence with mtDNA release induced by CSE exposure. Because high cf-mtDNA is detected in the plasma of COPD patients and serum of mice with emphysema, our findings support the future study of cf-mtDNA as a marker of mitochondrial stress in response to CS exposure and COPD pathology.

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