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Mitochondrial DNA is released by cigarette smoke

In a recent study, researchers have discovered that mitochondrial DNA is released extracellularly upon exposure to cigarette smoke and in COPD patients.

COPD and its risk factors

Chronic obstructive pulmonary disease (COPD) is a group of lung conditions that cause difficulties in breathing. It results in remodelling of airway wall thickness and pulmonary vasculature compromise. This in turns leads to long-term disability and early death. It is the third leading cause of death worldwide and accounts for around three million deaths per year. Alongside this substantial loss of life, COPD has a huge social and economic burden.  

COPD is caused by several factors, including genetic mutations, aberrant responses to bacterial and viral infections and/or exposure to indoor and outdoor pollutants, allergens, chemical toxins, and cigarette smoke. Cigarette smoke is the most common risk factor. While current therapies, such as corticosteroids and antibiotics, slow disease progression, there are still no existing treatments that prevent long-term lung decline. In addition, our current understanding of the mechanisms that drive inflammation remains unclear.

The role of mitochondrial DNA

Several studies have indicated that mitochondrial dysfunction is an important hallmark of COPD. Bioenergetic impairment, overproduction of reactive oxygen species and the accumulation of dysmorphic mitochondria are all common features in cells exposed to cigarette smoke. These features are also present in the epithelial cells of lung sections from COPD patients.

Mislocalisation of mitochondrial DNA (mtDNA) to the cytosol or extracellular space is known to trigger the innate system and thus trigger downstream proinflammatory signalling cascades. It is suspected that damage to mtDNA is a significant contributor to its mislocalisation.

Tracking mtDNA

In a recent study, published as preprint in biorxiv, researchers tested the hypothesis that exposure to cigarette smoke could promote extracellular mtDNA release, which could be detected in COPD.

The team specifically measured cell-free mtDNA (cf-mtDNA) in the plasma of former smokers affected by COPD. The researchers also measured this in the serum of mice that developed smoking-induced emphysema and in the extracellular milieu of human bronchial epithelial cells that were exposed to cigarette smoke extract. They found that patients with COPD and mice with emphysema had increased levels of cf-mtNDA.

They also found that when cells were exposed to sublethal doses of cigarette smoke extract, superoxide production and oxidative damage were increased, mitochondrial dynamics were dysregulated and mtDNA release in extracellular vesicles was triggered. In comparison, exposure to a lethal dose preferentially induced mtDNA and nuclear DNA release in cell debris.

Overall, these findings demonstrate that cigarette smoking-induced stress can trigger mtDNA release and is associated with COPD. By understanding the mechanisms of mtDNA extrusion and its extracellular role, may help to identify novel therapeutic targets for smokers and COPD patients.

Image credit: canva

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Lung Cancer / Mitochondria / Smoking