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Eur Respir J 2004; 23:214-218
Copyright ©ERS Journals Ltd 2004

Reversible inhibition of mitochondrial complex IV activity in PBMC following acute smoking

J-R. Alonso, F. Cardellach, J. Casademont and Ò. Miró

Mitochondrial Research Laboratory, Muscle Research Unit, Dept of Internal Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and University of Barcelona, Barcelona, Catalonia, Spain

CORRESPONDENCE: Ò. Miró, Muscle Research Unit, Dept of Internal Medicine, Hospital Clínic, Villarroel 170, 08036, Barcelona, Catalonia, Spain. Fax: 34 932279365. E-mail: omiro@clinic.ub.es

Keywords: carbon monoxide toxicity, cytochrome oxidase, mitochondrial diseases, smoking

Received: April 6, 2003
Accepted September 22, 2003

This study was supported by Promoción General del Conocimiento PM99-0038 and Premi Fi de Residència 1999 of Hospital Clínic i Provincial de Barcelona.


   Abstract
TOP
 Abstract
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Smoking causes a decrease of mitochondrial complex IV activity in chronic smokers. However, it is not known if this toxic effect is due to the acute effect of cigarette smoke itself or is a secondary phenomenon related to other smoking factors.

The study assessed mitochondrial respiratory chain function in peripheral blood mononuclear cells of 15 healthy nonsmoker individuals before smoking (t0), immediately after smoking five cigarettes in 45 min (t1) and 24 h later (t2). Blood carboxyhaemoglobin (COHb) and carbon monoxide concentrations in exhaled air (COEA) were determined to ascertain smoke inhalation status.

After acute smoking, COHb increased from 0.5±0.3% to 3.3±1.5%, and COEA from 2.9±2.5 to 26.1±9.9 ppm. Complex II and III enzyme activities did not change along the study. Complex IV activity showed a 23% inhibition at t1 but returned to initial (t0) levels at t2. A decay in oxygen consumption was observed after the correction for mitochondrial content. Lipid peroxidation of cell membranes remained unchanged.

Short-time smoking causes an acute and reversible mitochondrial complex IV inhibition in human mononuclear cells. These results suggest that smoke itself is one of the causes for the decrease of complex IV activity observed in chronic smokers.

Tobacco consumption causes damage in lungs and many other tissues and organs. Its devastating consequences are mediated by some of the >4,000 compounds contained in tobacco smoke 1. Some of these compounds constitute themselves a major exogenous source of reactive oxygen species (ROS), as well as exhibiting a capacity for increasing endogenous ROS production via activation of inflammatory-immune processes 2. The major consequence for cell biology of the increase in ROS content is to enhance oxidative damage of some biological molecules of crucial relevance for cellular functions, such as deoxyribonucleic acid (DNA), proteins and lipids, which leads to a deterioration or loss of their physicochemical properties and functions 3. Increasing attention has been paid in the recognition of relevance that such an oxidative damage could play in tobacco-mediated diseases, since greater lipid peroxidation 4, DNA oxidation and DNA repair activity 5–7 have been demonstrated in smokers compared with nonsmokers 8.

Mitochondria are one of the most important endogenous sources of ROS, since side reactions of the mitochondrial respiratory chain (MRC) with molecular oxygen (O2) directly generate such toxic oxygen metabolites 9. Some of the chemicals contained in tobacco smoke have been suggested to interfere with different compounds of the MRC electron transport 10, which could result in an increased production of ROS. However, to date there have been few studies on the relationship between tobacco consumption and mitochondrial activity in humans.

It has been recently demonstrated by the authors that a decrease in mitochondrial cytochrome c oxidase activity in peripheral blood mononuclear cells (PBMC) from chronic smokers was associated with an increased membrane lipid peroxidation 11. However, it is not known if such decrease in cytochrome c oxidase activity is due to the effects of tobacco smoke itself or, alternatively, it is a collateral event associated with damage in other organs induced by the smoking habit. In order answer this question, in the present study the authors investigated the acute effects of smoking in MRC from human PBMC. If acute smoking has effects on MRC function, it would implicate that such mitochondrial dysfunction could be of pathophysiological relevance in some smoking-related diseases.


   Subjects and methods
TOP
 Abstract
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Subject selection
A total of 20 nonsmoking young healthy subjects with similar physical activity 12, 13 were selected, recruited by an advertisement in the University of Barcelona Campus. All subjects gave their informed written consent to be included in the study. The Ethical Committee of the Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, approved the protocol.

Proceedings
The 20 selected subjects were allocated to a diet without anexcess of antioxidants for 2 weeks 14, 15. Sincerity about nonsmoker status was ascertained by means of two nonprogrammed determinations of carboxyhaemoglobin (COHb) levels (Blood gas Analyzer CIBA-CORNING 800 System; Basel, Switzerland) and carbon monoxide in exhaled air (COEA) levels by means of an electrochemical transducer (Dräger Pac III; Dräger Safety Inc, Pittsburgh, PA, USA). All subjects had COHb levels <2% and COEA <6 ppm. After this period, subjects smoked five filtered cigarettes (nicotine 0.8 mg, tar 11 mg) in 45 min. Individuals who did not increase by three times their basal levels of COHb at the end of the smoking (n=5) were excluded.

In all 15 remaining subjects (25±4 yrs; nine males) COEA was determined and 30 mL of peripheral blood was obtained before smoking (t0), 1 min after the last cigarette (t1) and 24 h later (t2). COHb levels were measured with 3 mL of each sample. PBMC (lymphocytes and monocytes) were isolated by means of Ficoll's gradient. The final protein concentration was quantified according to Bradford's method 16.

Mitochondrial assays
PBMC was chosen for mitochondrial assays as it is a standard procedure for the investigation of respiratory chain disorders in humans 17, is a minimally invasive test for volunteers, and would establish the relationship of COHb levels with COEA levels.

Enzyme activity
Measurement of enzyme activity of individual complexes of the MRC was performed spectrophotometrically (UVIKON 920; Kontron, Schlieren, Switzerland). Complex II, III, and IV activities were determined following Rustin et al. 17 methodology, slightly modified for complex IV measurement 18. Complex I and V cannot currently be accurately measured in PBMC 17.

Oxidative activity
O2 utilisation was measured polarographically in 250 µl of standard medium (pH 7.4) with a Clark electrode in a water-jacketed cell at 37°C (Hansatech Instruments Limited®, Norfolk, UK) according to Rustin et al. 17.

Correction of absolute activities by mitochondrial content (relative activities)
Relative activities were established by dividing absolute enzyme and oxidative activities by citrate synthase activity 19, 20, which was assessed spectrophotometrically 17.

Peroxidation of lipid membranes
Loss of cis-parinaric acid fluorescence was used to measure lipid peroxidation 21. PBMC protein (100 µg) was put in 3 mL of phosphate buffered serum containing cis-parinaric acid (5 mM) (Molecular Probes®, Eugene, OR, USA). Loss of fluorescence was measured with a fluorescence spectrophotometer (Hitachi F-2000, Tokyo, Japan) in the dark at 37°C for 30 min at 3 min intervals.

Statistical analysis
Mean±sd and percentages were used for quantitative and qualitative variables, respectively. Comparisons between results at t0, t1 and t2 were carried out using a paired t-test after assessing the normality of the distribution (Kolmogorov-Smirnov's test) and the equality of variances (Levene's test). An ANOVA model for repeated measures was used for comparison of cis-parinaric fluorescence curves at t0, t1 and t2 to search for intergroup differences with time. Values of p<0.05 were considered statistically significant.


   Results
TOP
 Abstract
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
COHb levels of participants increased from 0.5±0.3% at basal conditions (t0) to 3.3±1.5% immediately after smoking (t1) (p<0.001). An identical pattern was recorded for COEA, which rose from 2.9±2.5 ppm (t0) to 26.1±9.9 ppm (t1) (p<0.001). According to these findings, cigarette smoke inhalation was considered effective. At t2, both markers of tobacco smoke exposition returned to initial (t0) values (0.6±0.3% for COHb and 3.9±2.3 ppm for COEA; nonsignificant difference with respect to t0 levels for both).

PBMC and mitochondria content did not differ along the times of study in the different samples. PBMC content (mg ofprotein·mL–1) was 15.3±3.6 at t0, 13.98±4.21 at t1 and 14.2±5.0 at t2 (nonsignificant difference), and cytrate syntase activity (nmol·min–1·mg–1 of PBMC protein) was 143.4±35.8 at t0, 145.3±45.3 at t1 and 134.9±36.7 at t2 (nonsignificant difference).

Effects of smoking on MRC are showed in figures 1 and 2GoGo. Smoking caused an immediate decrease of complex II, III and IV enzyme activities, but the decrease was statistically significant only for complex IV (cytochrome c oxidase), which decreased from 49.4±17.1 nmol·min–1·mg–1 protein at t0 to 38.1±11.7 at t1 (p=0.002), and returned to basal levels 24 h later (50±19.3 nmol·min–1·mg–1 protein at t2) (fig. 1aGo).



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  		Fig. 1.— a) Absolute enzyme activities and b) relative enzyme activities. {square}: before smoking; : immediately after smoking; : 24 h after smoking. #: nonsignificant difference; : p=0.002; ***: p<0.001.

 


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  		Fig. 2.— a) Absolute oxidation rates and b) relative oxidation rates. O2: oxygen. {square}: before smoking; : immediately after smoking; : 24 h after smoking. #: nonsignificant difference; : p=0.01; *: p<0.05; **: p<0.01.

 
After the correction of absolute enzyme rates by citrate synthase activity in order to obtain their relative activities, again only cytochrome c oxidase activity showed a same pattern of decrease associated with acute smoking, which decreased from 34.7±8.4% at t0 to 25.7±7.1% at t1 (p<0.001) (fig. 1bGo).

Study of O2 consumption by PBMC showed no changes in spontaneous cell respiration or substrate oxidation with time when absolute activities were considered (fig. 2aGo). However, according to relative oxidative activities (fig. 2bGo), an overall decrease of O2 consumption after smoking (t1) was observed with all substrates, when compared with t0 values, being significant with pyruvate (p=0.01) and glycerol-3-phosphate (p<0.01). In spite of this decrease of O2 consumption, a tendency to enhance spontaneous cell oxidation rate (fig. 2bGo), that became significant at t2 was observed.

Finally, the study of lipid peroxidation of peripheral mononuclear cell membranes showed the same curves of loss of fluorescence of cis-parinaric acid before smoking, immediately after smoking, and 24 h after smoking (nonsignificant difference) (fig. 3Go).



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  		Fig. 3.— Curves of fluorescence of cis-parinaric acid. {square}: before smoking; {circ}: immediately after smoking; {triangledown}: 24 h after smoking. Error bars show sd.

 

   Discussion
TOP
 Abstract
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
The present study investigated the effects of acute smoking on MRC components of PBMC in healthy, nonsmoking subjects with a similar physical activity 12, 13 and illness was excluded by means of medical history, physical examination and routine blood analyses. Smoke inhalation was clearly effective in the studied individuals, as judged by the increase of COHb and COEA levels following smoking 22–24. Subjects were assumed to have absorbed enough carbon monoxide (CO) to detect any potential change in the studied parameters. On these experimental premises, a significant inhibition in absolute (23%) and relative (30%) cytochrome coxidase activity was observed. With regard to relative oxidative activities, O2 consumption with pyruvate and glycerol-3-phosphate substrates showed a significant inhibition according to citrate synthase activity. All mitochondrial changes disappeared after 24 h of smoking abstinence, when blood COHb and COEA levels had also returned to basal values. These findings cannot be explained by any variability in the mitochondrial yield of samples at different times of the study, since citrate synthase activity was similar in all of them. Therefore, the observed effects should arise from direct and/or indirect actions of one or more of the components of tobacco smoke.

Gvozdjáková et al. 25 and Gvozdjak et al. 26 demonstrated a decrease in cytochrome c oxidase activity of heart muscle mitochondria from rabbits inhaling cigarette smoke and noted that this decrease was higher in proportion to the length of the smoke exposure. In humans, Örlander et al. 27 and Larsson and Örlander 28 found a decrease in cytochrome c oxidase activity from skeletal muscle mitochondria from chronic smokers, but did not give any information about MRC function after smoking cessation. More recently, the current authors have reported that tobacco is a confounding factor in studies concerning MRC function 12 and have demonstrated a 23% inhibition of cytochrome c oxidase activity in PBMC of heavy smokers with an average COHb of 4.8% 24. Therefore, data from the current study from nonsmokers adds further evidence to previous studies and clearly indicates that smoking itself causes an immediate and transient alteration of cytochrome c oxidase activity.

The overall results of the current study have shown a 23% inhibition of cytochrome c oxidase, together with a significant decrease in the O2 consumption of MRC for pyruvate and glycerol-3-phosphate substrates and a nonsignificant change in succinate substrate, as well as significant enhanced spontaneous respiratory activity in intact PBMC after 24 h of smoking cessation. This increase in cell respiration was an unforeseen finding because it occurred 24 h after smoke exposure, when the remainder of MRC parameters were already normal. Hypothetical steps at which such an up-regulation could occur include changes in nonmitochondrial oxidation, adenosine triphosphatease activity and/or mitochondrial proton leak 24. In any case, those results suggest that such a degree of cytochrome c oxidase inhibition in short-time smoke inhalation is high enough to cause a disturbance of mitochondrial oxidative processes and a measurable but reversible decay in mitochondria energy production.

Although pathological effects after chronic exposure to some chemical agents are not always mediated through the same cellular and molecular pathways as an acute reaction, in the acute model of smoking in the current study a similar MRC inhibition was found to that in chronic smokers 24. However, in the authors' opinion the ultimate toxic effect of smoking is more severe in chronic exposure, since enhanced lipid peroxidation was found in heavy smokers 24, though not after acute smoking, indicating ultimately a failure in the adaptative processes in heavy smokers. Therefore, the effect of cytochrome c oxidase inhibition on cell function in vivo in long-term smoking, together with other many disturbing tobacco-related factors, such as hypoxia, vitamin and antioxidant deficiencies, cyanide and other toxic substances, could contribute to an overall decrease of oxidative capacity, resulting in high free-radical production, mitochondrial DNA damage and cell death or proliferation 29–31. All these events would be especially harmful in target organs and tissues, such as the lungs and bronchial epithelium.

The specific relevance of this cytochrome c oxidase inhibition in whole-cell metabolism remains unclear, since cells normally use only 10–20% of the maximal velocity of an enzymatic reaction of the enzyme, and therefore to inhibit cellular respiratory rates a greater inhibition than that observed would be needed. Although this MRC dysfunction cannot be explained by the pathophysiology of smoking consequences, the authors believe that chronic and persistent inhibition should be considered as another factor in cellular injury, especially in cells already damaged by other physiopathological mechanisms of cigarette smoke. Additionally, the effects of tobacco smoke (either acute or chronic) are not exerted equally on all tissues. For example, respiratory tract epithelium and the lungs have a higher exposure to the physical and chemical effects of tobacco compounds, while consequences in other organs are related to their energy dependence status. Thus, in respiratory tract epithelium and the lungs, a higher enzyme activity inhibition could lead to a higher mitochondrial dysfunction that could contribute to less removal of bronchial secretions (due to bronchial epithelium ciliar misfunction), less response to infections (due to macrophage misfunction), and carcinogenesis 32, 33. Moreover, in high energy dependent tissues, such as the brain, heart and muscle, an abnormal cytochrome c oxidase activity could contribute to the damage associated with tobacco consumption via a chronic decrease on whole mitochondria oxidative capacity 27, 28, 34–37. Finally, as seen in many hypoxic circumstances 38, arteriopathy and chronic obstructive pulmonary disease could also contribute to mitochondrial injury.

Some authors have suggested that CO could be responsible for the decrease of cytochrome c oxidase activity 27. This hypothesis is supported by the findings in patients suffering from acute, pure CO poisoning (COHb levels ~20%), in whom a severe and persistent inhibition of cytochrome c oxidase activity of 50–90% was demonstrated. This has been recently confirmed in vitro 39. The binding of CO to cytochrome aa3, a component of cytochrome c oxidase, is the responsible for its deleterious effect 40–42 on this MRC enzyme 11. Since acute smoking could be considered as atype of acute CO poisoning, although not pure (other components of cigarette smoke, such as cyanide 43, could also contribute to cytochrome c oxidase inhibition) and of a lower intensity, the authors believe that most considerations generally accepted for true CO poisoning could also apply for some disturbances that subjects with a chronic smoking habit will develop.

In conclusion, the decrease of mitochondrial complex IV activity that was found in peripheral blood mononuclear cells from acute smokers suggests that smoke itself is one of the causes of some enzyme inhibition observed in chronic smokers. However, the ultimate consequences of such long-term enzyme inhibition in tobacco-related diseases of the lung and other tissues in chronic smokers remain to be established.


   Acknowledgements
TOP
 Abstract
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors would like to thank A. Beato and S. López their valuable technical support.


   References
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 Abstract
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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