Mitochondrial DNA Content Increase in Response to Cigarette Smoking

Abstract

An increase in mitochondrial DNA (mtDNA) content and decline in mitochondrial function occurs with aging and in response to DNA-damaging agents, including tobacco smoke. We did a cross-sectional study and quantified changes in mtDNA content in a population of individuals with varied smoking and alcohol exposure. Age, smoking history, ethanol intake, and other demographic data were characterized for 604 individuals participating in a screening study for smoking-related upper aerodigestive malignancy. Total DNA was extracted from exfoliated cells in saliva. DNA from a nuclear gene, b-actin, and two mitochondrial genes, cytochrome c oxidase I and II (Cox I and Cox II), were quantified by real-time PCR. mtDNA content was correlated with age, exposure history, and other variables using multivariate regression analyses. A significant increase (P < 0.001) in mtDNA content was noted in smokers (31% and 29% increase for Cox I and Cox II, respectively) and former smokers (31% and 34%) when compared with never smokers. This association persisted after adjustment for other significant factors including age, alcohol drinking, and income (P < 0.001). Increased mtDNA content was positively associated with pack-years of smoking (P = 0.02). Despite an average smoking cessation interval of 21 years in former smokers, tobacco cessation interval was not statistically significantly associated with mtDNA content. Smoking is associated with increased mtDNA content in a dose-dependent fashion. Mitochondrial DNA alterations in response to smoking persist for several decades after smoking cessation, consistent with long-term, smoking-related damage. (Cancer Epidemiol Biomarkers Prev 2006;15(1):19 -24)

Mitochondrial Dysfunction in Atherosclerosis

“…182,183 Atherogenic effects of cigarette smoking include endothelial injury, platelet activation, oxidation of LDL, and oxidative DNA damage. 183,184 Consistent with the cumulative and residual risk of cigarette smoking on atherosclerosis, a significant increase in mtDNA content was reported in the saliva of smokers and former smokers compared with never smokers 185 and increase in mtDNA content is accompanied by mtDNA deletions, evidence of oxidative damage, decreased transcription of mitochondrial-specific proteins, and apoptosis. 186 -188 Significant decrease in complex IV activity of mitochondrial respiratory chain and increase in lipid peroxidation of lymphocyte membranes were observed in circulating lymphocytes from smokers compared with nonsmokers.…”

Contribution of Endogenous Inhibitor of Nitric Oxide Synthase to Hepatic Mitochondrial Dysfunction in Streptozotocin-induced Diabetic Rats

“…ATP concentrations were detected by bioluminescence assay based on the reaction of ATP with recombinant firefly luciferase and its substrate luciferin [25]. Rat liver (0.5 g) was homogenized in 1:10 wt/vol of ice-cold lysis buffer or cultured hepatocytes were lysed in an ice-bath and then centrifuged at 12,000 g for 5 10 min (4°C), the resulting supernatant was used immediately for the analysis of ATP content, which was normalized to supernatant protein concentration.…”

“…Among these respiratory enzymes, complex II (succinate dehydrogenase) and complex IV (cytochrome C oxidase) are also key enzymes in mitochondrial respiratory chain [3]. Furthermore, mitochondrial function is also related to mitochondrial biogenesis [4], which is often mirrored by the copy number ratio of mitochondrial genes such as cytochrome C oxidase subunit I (COX I) to nuclear genes like -actin indirectly [5]. Most investigations about mitochondrial dysfunction in diabetes mellitus are focused on skeletal muscle [2,4] and fat tissue [6] while few in liver.…”

Sustained hypoxia modulates mitochondrial DNA content in the neonatal rat brain

“…In the mature organism, mitochondrial biogenesis may occur as a compensatory mechanism in compromised oxygenation including, chronic pathological states, acclimatization to high altitude, and intense exercise [10][11][12][13], as well as long-term inhalation of cigarette smoke [14]. Interestingly, in the aging brain, increased mtDNA content may coincide with reduced mitochondrial RNA levels, suggestive of inefficient compensatory mechanism, inadvertently contributing to aging of the brain [15].…”