Next Article in Journal
The Regulatory-T-Cell Memory Phenotype: What We Know
Next Article in Special Issue
Upregulated Ca2+ Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease
Previous Article in Journal
Proteostasis Response to Protein Misfolding in Controlled Hypertension
Previous Article in Special Issue
Long-Term Dynamic Changes of NMDA Receptors Following an Excitotoxic Challenge
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Alterations of Mitochondrial Network by Cigarette Smoking and E-Cigarette Vaping

College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA
Department of Pharmaceutical Chemistry, Geethanjali College of Pharmacy, Cherryal, Keesara, Medchalmalkajgiri District, Hyderabad 501301, India
Department of Physics, University of South Florida, Tampa, FL 33620, USA
Department of Zoology, School of Life and Health Sciences, Adikavi Nannaya University, Rajahmundry 533296, India
Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Authors to whom correspondence should be addressed.
Cells 2022, 11(10), 1688;
Submission received: 17 April 2022 / Revised: 13 May 2022 / Accepted: 16 May 2022 / Published: 19 May 2022


Toxins present in cigarette and e-cigarette smoke constitute a significant cause of illnesses and are known to have fatal health impacts. Specific mechanisms by which toxins present in smoke impair cell repair are still being researched and are of prime interest for developing more effective treatments. Current literature suggests toxins present in cigarette smoke and aerosolized e-vapor trigger abnormal intercellular responses, damage mitochondrial function, and consequently disrupt the homeostasis of the organelle’s biochemical processes by increasing reactive oxidative species. Increased oxidative stress sets off a cascade of molecular events, disrupting optimal mitochondrial morphology and homeostasis. Furthermore, smoking-induced oxidative stress may also amalgamate with other health factors to contribute to various pathophysiological processes. An increasing number of studies show that toxins may affect mitochondria even through exposure to secondhand or thirdhand smoke. This review assesses the impact of toxins present in tobacco smoke and e-vapor on mitochondrial health, networking, and critical structural processes, including mitochondria fission, fusion, hyper-fusion, fragmentation, and mitophagy. The efforts are focused on discussing current evidence linking toxins present in first, second, and thirdhand smoke to mitochondrial dysfunction.

1. Introduction

Cigarette smoking (CS), e-cigarette (EC) vaping, and other types of exposure to environmental tobacco smoke, including second and thirdhand smoke, are dangerous to human health, causing diseases that affect every organ system [1,2,3,4]. Despite thorough documentation of the extensive damages caused by smoking, it continues to be one of the most prevalent public health concerns worldwide, claiming millions of lives each year [2]. Primary and secondary exposure to tobacco smoke significantly raises the risk of cancer [5,6,7], coronary heart disease [8,9,10] stroke [11,12], and bacterial and viral infections, and has detrimental impacts during pregnancy [13,14,15].
The detrimental effects of tobacco smoke are not limited to smokers. Non-smokers exposed to second and thirdhand smoke in the environment also show an increased risk for health concerns [4]. Cigarette smoke is composed of thousands of chemicals, of which many are volatile, carcinogenic, and cause DNA damage [16,17,18]. These chemicals can reside in the environment until inhaled by non-smokers to continue causing devastating health impacts. Secondhand smoke (SHS) is a mixture of what is exhaled by the smoker and what is emitted by the burning tobacco product, whereas thirdhand smoke (THS) is the residue that accumulates from SHS deposited onto surfaces and can exist in the environment for a long time.
E-cigarettes, also known as electronic nicotine delivery systems (ENDS), were first introduced and marketed as a healthier alternative to cigarettes and to help with smoking cessation [19]. However, new dangers continue to present themselves as ENDS use continues to rise among young adults and adolescents [20]. E-cigarette liquid (e-liquid) is composed of various agents, typically a solvent, nicotine and additional flavoring compounds suspended in a humectant inhaled as an aerosol [21]. Despite the original intention to reduce the detrimental impacts of tobacco smoking, ENDS are largely unregulated and pose increasing concerns as they are proving to be toxic for neonates [19,22], vascular health [23,24], respiratory health [25], and damaging to the oral cavity [26].
This paper discusses the pathophysiological mechanisms by which toxicants from tobacco smoke and ENDS negatively impact mitochondrial function. Mitochondria play a vital role in redox signaling [27], cell cycle regulation, differentiation, DNA exchange between cells to restore function, and apoptosis. As a result of their critical role in cell survival and proliferation, mitochondria are often an organelle of interest when studying cellular mechanisms impacting multiple disease processes. Furthermore, mitochondrial susceptibility to damage by exposure to toxicants justifies investigating the impact of environmental chemicals on the organelle [28]. The effects of inhaled toxicants can include inhibition of ATP synthesis due to uncoupling of oxidative phosphorylation [29], increased oxidative mitochondrial damage [30], and mitochondria-initiated apoptosis [31].
Disruptions in mitochondrial function can result from impaired morphology, fusion and fission imbalances, increased oxidative stress, or even mutations within the mitochondrial DNA (mtDNA). Impaired mitochondrial morphology and function are implicated in the pathogenesis of pulmonary [32], neurodegenerative [33], and diabetic kidney diseases [34], and can be pro-tumorigenic [35], and potentiate inflammatory responses [36]. Mitochondrial DNA, a circular chromosome found within the organelle maintained by nuclear-encoded proteins [37], is another component that can contribute to disease if damaged [38]. Mutations in mitochondrial DNA are responsible for numerous diseases, such as optic atrophy [39], mitochondrial myopathy [40], and diabetes mellitus [41].

2. The Mitochondrial Fusion and Fission Machinery

The mitochondria’s dynamic and healthy nature is dependent on inter-organelle crosstalk and key processes, including mitochondrial fusion, fission, mitoptosis, and mitophagy [42,43,44,45]. The joint forces of mitochondrial fusion and fission, maintained by dynamins and mitofusins, support robust and optimal network morphology [29,46,47], and respond to physiological conditions [48]. On the contrary, an imbalance in the proteins determining mitochondrial dynamics can aggravate type 2 diabetes [49], neurodegenerative diseases [50,51], and can be embryonically lethal [52,53].
Defective mitochondria are disposed of through mitochondrial fission [54], whereas mtDNA exchange and rescue of damaged mitochondria can happen through fusion [55]. The dynamin superfamily contains a variety of ubiquitous GTPases involving multiple processes, including regulating mitochondrial fission. Dynamin-related protein 1 (Drp1) is known to play a critical role in mitochondrial homeostasis by forming fission rings to eliminate damaged parts of the mitochondrial membrane. Drp1 binding requires the presence of different proteins, including Mitochondrial Fission 1 Protein (FIS1) on the outer mitochondrial membrane, mitochondrial dynamics proteins 49kDa (MiD49), 51 kDa (MiD51) [56], and mitochondrial fission factor (MFF) [57]. Mitochondrial fusion is dependent on the presence of another class of GTPases known as mitofusins [58]. Mitofusins 1 and 2, located at the outer mitochondrial membrane, reciprocally interact with Drp1 to enable fusion [59], support proper embryological development and enhance mitochondrial cooperation to prevent respiratory dysfunction [53]. The mitochondrial dynamin-like GTPase, Optic atrophy 1 (OPA1), is located on the inner mitochondrial membrane (IMM). OPA1 exists in many isoforms that work together to induce mitochondrial fusion [60]. When there is a loss of membrane potential longform OPA1 isoforms become destabilized and can no longer optimally function [60]. We demonstrate mitochondrial fusion and fission in cartoon Figure 1.
Apart from fusion and fission, mitophagy is another critical process that degrades mitochondria through autophagy. PTEN-induced putative kinase 1 (Pink1) initiates the clearance of defective mitochondria through mitophagy. This clearance pathway is initiated in various pathological conditions [61,62,63] to protect the organelle from dysfunction. Pink1 accumulates on the outer mitochondrial matrix of dysfunctional mitochondria. The increased Pink1 concentration consequentially recruits Parkin, an E3 ubiquitin ligase. The Pink1/Parkin complex acts as marker signaling the defective organelle for clearance by mitophagy. Consequentially, mitophagy is quintessential to protecting optimal mitochondrial form and function and operates on multi-tiered processes [64,65]. Failure to initiate mitophagy, or reduction in its process, promotes mitochondrial oxidative stress. This failure sets off a cascade of imbalanced signaling pathways, which can accelerate disease processes, including neurodegenerative and cardiovascular conditions [66,67,68].

3. Cigarette Smoke and E-Cigarette Vape Extraction

In vitro effects of cigarette smoke and e-cigarette vapor are best studied through cell culture media, and consequently various systems have been developed over time to accommodate studies conducted in larger or smaller chambers. We will quickly review two examples of how extraction systems are set up. SV Teague et al. developed a method for smaller chambers that is specifically useful for maintaining consistent levels of total suspended particles to replicate better relevant environmental conditions of smoke exposure [69].
CS or EC vaping machines contain cigarette or EC holding and lighting devices. A metered puff controller regulates the number of smoke or vape puffs through a flow machine, and chimneys in the conditioning chamber dilute smoke puffs to distribute smoke to each chamber containing animal or cell-culture media [70]. Abouassali O et al. extracted e-vapor in cell culture media to study the in vitro toxicity of flavored e-liquids [70]. A 10-cm × 10-cm × 7-cm chamber was made with a bottom opening fitted for the vaping device’s mouthpiece. The chamber contained inlet and outlet openings on the top of the lid. The inlet tube received air through an air pump connected to a flow meter, whereas the outlet tube delivered the e-vapor to the cell culture media. Regulating the vacuum connected to the flow meter enabled control of puff size and led to vapor bubbling into the cell culture medium [70].

3.1. Cigarette Smoke (CS) and Cigarette Smoke Extract (CSE) Trigger Mitochondrial ROS

Mitochondrial reactive oxygen species (mtROSs) are invaluable intermediates of cell signaling pathways. Their production integrates various biochemical processes to sustain cell survival, signaling, and energetics [71]. In addition to making ATP, the electron transport chain maintains the organelle’s electrochemical potential, which signals the proper function and integration of other metabolic and cellular processes. Disruption in one or more of the processes supporting healthy mitochondrial populations and networking has multifaceted implications and can disrupt the organelle’s ability to regulate ROS levels. In excess, mtROS can contribute to mitochondrial dysfunction and many diseases [72,73,74]. This undeniable influence of mtROS on other signaling pathways is a key mechanism often implicated by inhaled toxicants [32,75,76,77].
Wang Z et al. found that CS increased oxidative stress, reduced respiration, and disrupted the balance of mitochondrial fusion and fission, resulting in altered mitochondrial morphology in primary rat lung microvascular endothelial cells (LMVEC) [78]. One of the ways CS altered mitochondria was by shortening the organelles’ network and making it smaller. These smaller networks of damaged mitochondria were more prone to perinuclear accumulation. CS disrupted the balance of fission and fusion events by upregulating mitochondrial fission and decreasing fusion. Increased mitochondrial fission resulted from decreasing Drp1-S637 and increasing FIS1, Drp1-S616 phosphorylation [78]. On the other hand, CS-mediated Mfn2 reduction in LMVEC and mouse lungs resulted in reduced mitochondrial fusion. In addition to altered fission and fusion events, CS also induced mitochondrial translocation and tetramerization [78].
In healthy non-smokers, acute THS exposure increased oxidative stress and upregulated ROS scavenging genes in human nasal epithelial cells [79]. Compared to healthy non-smokers, smokers had increased somatic mtDNA mutations in their buccal cells [80]. Not only is mtDNA susceptible to oxidative damage, but the mutations themselves can target the cytochrome c oxidase subunit 1 complex [80]. Cigarette smoke extract (CSE), in vivo, has been shown to increase oxidative stress and reduce mitochondrial membrane potential in human fetal fibroblast strains and human lung fibroblast HFL-1 and L828 [81]. Morphologic characteristics of apoptotic cell death were seen after incubating fibroblasts with 10% CSE for six hours [81]. Exposure to 5% CSE at 3 h initially reduced glutathione (GSH) levels, consequently reducing the organelle’s antioxidant capacity. The lipophilic components of CSE disrupt mitochondrial function in bronchial epithelial cells by causing a dose-dependent decrease in mitochondrial membrane potential and intracellular ATP levels while also increasing ROS [82]. Low dose CSE triggers proadaptive survival mitochondrial hyper-fusion in mouse alveolar epithelial cells. These changes appear to play a protective role in maintaining the organelle’s function during initial stages of exposure [83]. These structural changes were seen with increased levels of MFN2 within 24 h of 10% or 20% CSE treatment [83].
Interestingly enough, these proadaptive mitochondrial morphology changes were accompanied by increased metabolic activity and ATP levels without causing an increase in mitochondrial superoxidases [83]. The studies thus far indicate the important role that dosage and exposure to CS play. Initial responses triggered by CSE are primarily protective. However, these protective changes can lead to irreversible damage or exacerbate pathological processes in dose and time-dependent manners.
CSE exposure in human bronchial epithelial cells (HBECs) caused mitochondrial fragmentation and increased mitochondrial ROS production, leading to an increased percentage of cellular death [84]. Hara et al. found that the HBEC mitochondria in COPD lung tissue were more prone to fragmentation, indicating that preexisting conditions increase the organelle’s susceptibility to damage by CSE. Whole cigarette smoke condensates (WCSCs) decreased cell viability in the normal human bronchial epithelial cell line (BEAS-2B) in a dose-dependent manner and disrupted mitochondrial homeostasis by inducing hypoxic conditions [85]. WCSC caused a clear dose-dependent elevation of IL-6 and IL-8, and increased ferritin protein expression. Increased levels of apoptosis, autophagy, ER stress, antioxidant, and MAP kinase activation-related proteins suggested WCSC may induce ferroptosis through disrupting homeostasis.
In human airway smooth muscle, CSE increased Drp1 and reduced mfn2 in a concentration-dependent fashion [59]. These changes induced mitochondrial fragmentation and damaged morphology by reducing mitochondrial branching and branch length [59]. Furthermore, Aravamudan et al. showed how fusion-fission protein disruption could negatively influence ROS production, cell proliferation, and apoptosis in airway diseases, such as asthma and chronic obstructive pulmonary disorder (COPD) [59]. Long-term CSE in COPD primary bronchial epithelial cells induced mitochondrial fragmentation and altered morphology by reducing the number of cristae [86]. These changes in morphology were noted alongside increases in oxidative stress markers, OXPHOS proteins, proinflammatory mediators, and expression of fission and fusion markers.

3.2. The Role of Nicotine in Mitochondrial Dysfunction

Nicotine is richly present in tobacco products. Nicotine is one of the many thousands of compounds present in cigarette smoke and is commonly found in ENDS [87]. CS and ENDS produce nicotine boli which are transported to the central nervous system and activate nicotinic acetylcholine receptors (nAChRs) [87], present throughout the body. The interaction between nicotine boli and nAChRs can modulate mitochondrial dynamics in hippocampal neurons [88], in lung cancer [89,90], and can impact fetal and neonatal development [91].
A previously done western blot analysis revealed that 10 µM of nicotine induced mitochondrial fragmentation in human multipotent embryonal carcinoma cell line NT2/D1, by significantly decreasing Mfn1 and Mfn2. This effect is based on an unknown mechanism [92]. Hirata et al. confirmed the mechanism by using a nonselective nAChR antagonist, which effectively blocked nicotine-induced reduction of Mfn1 and Mfn2 protein levels, ATP levels, and mitochondrial fragmentation. Guo et al. proved that in non-small cell lung cancer cells, nicotine-induced activation of hypoxia-inducible factor (HIF)-1α was dependent on mitochondrial-dependent ROS activating downstream Akt and MAPK signaling pathways, as well as transcriptional regulation, via factors such as NF-κB and nuclear erythroid 2-related factor 2 [59,89]. The CSE decrease of mitochondrial fusion by decreasing Mfn2 and elevating fission by elevating Drp1 causes mitochondrial fragmentation. Optimal mitochondria numbers are required to generate the ATP for cellular demand, and an imbalance of mitochondrial fusion and fission elevates cellular ROS. We demonstrate this in Figure 2. Maternal nicotine, regardless of cigarette smoking or nicotine replacement therapy, induces oxidative stress targeting the mitochondria, as well as β-cell apoptosis in the pancreas, negatively impacting the offspring [91].

3.3. Constituents of Fluids Used in ENDS Are Cytotoxic and Impair Mitochondrial Function

As the number of flavors available for e-cigarettes continues to increase, more studies must be done to understand the impact of various flavors and solvents on health [94]. Currently, studies present evidence for the varying toxicity of different flavors, indicating the need to generate a profile of which compounds could be more toxic [70,95,96,97]. Specific studies exploring the toxicity of flavors on mitochondria are limited. However, some of these flavors and their toxicities will be discussed in this section before further expanding on studies specific to mitochondrial function.
Cinnamaldehyde or vanillin-flavored e-vapor was toxic in HL-1 cardiomyocytes and compromised cardiac electrophysiology [70]. Abouassali et al. set up a vaping chamber that expelled a puff volume of 110 mL set on a cyclical timer to mimic ENDS user consumption. After ten weeks of inhaling vanillin-aldehyde e-vapor, an increased sympathetic variance was noted in heart rate. In vivo inducible ventricular tachycardia and the magnitude of ventricular action potential duration alternans were respectively more prolonged and larger in vanillin-flavored e-vapor exposed mice. HL-1 atrial cardiomyocytes are more susceptible to necrosis and apoptosis when cultured with vanilla-custard e-vapor extract in a concentration-dependent manner. Mitochondria play a critical role in maintaining cardiomyocyte homeostasis. Therefore, more studies exploring the mechanistic connection between the impact of e-vapor on mitochondria and cardiomyocytes could prove invaluable. H292 human bronchial epithelial cells exposed to strawberry-flavored e-vapor had reduced metabolic activity, reduced cell viability, and increased interleukin release [95]. Cooper et al. demonstrated how vaping-related reinforcement behavior is elevated in male mice when self-administering menthol or green-apple flavored e-liquid compared to no flavor e-liquids [96]. Farnesol, a component of green apple flavor, has been shown to significantly increase nicotine-reward related behavior by altering baseline firing of GABA neurons and upregulating nAChR function, especially in male mice [97]. Interestingly enough, although ENDS are commonly advertised as a safer alternative to cigarette smoking, ECE was found to cause cardiomyocyte toxicities and generate oxidative stress similar to CSE [98]. Jabba et al. demonstrated that solvent adducts of reactive flavor aldehydes are more cytotoxic on lung epithelial cells (BEAS-2B and A549) than their parent aldehydes, due to the rapid chemical reaction they undergo with e-liquid solvents, propylene glycol, and vegetable glycerol (PG/VG). Furthermore, these reactive flavor aldehydes reduced mitochondrial ATP synthesis and were more cytotoxic than their parent aldehydes [99]. When compared to parent aldehydes, benzaldehyde PG, vanillin PG, and ethyl vanillin PG reduced mitochondrial oxygen consumption rate in a concentration-dependent manner with more potency [99]. This suggests the importance of looking at secondary reaction products and not just the parent compound when assessing cytotoxicity of EC fluids. Williams et al., demonstrated that MTT assay marked the cytotoxicity of two potent chemical toxins in EC solvents, selenium and arsenic. Both chemicals inhibited mitochondrial reductases in BEAS-2B cells and proved toxic for pulmonary fibroblasts, whereas selenium increased superoxide production in mitochondria [100]. In this particular study, selenium was present in all products, whereas arsenic was present in a few. This consideration brings awareness to a major concern regarding the variability in metals and metalloid concentrations present in EC liquid. This variability depends on the manufacturing company, packaging, coil type, and where the EC was purchased or obtained [101]. Depending on the user, the amount of vapor inhaled can also vary. This lack of consistency points to a significant need for regulation around manufacturing and distribution protocols to better understand the risk of exposure to different metals.

4. Maternal Health

The dangers of smoking during pregnancy have long been elucidated, and smoking cessation is advised for the duration of pregnancy. If smoking cessation is impossible, replacing cigarettes with EC is generally advised. There is a prevalent perception of ENDS being safer than smoking cigarettes. However, their use must be monitored during pregnancy [102]. Currently, there is insufficient data to understand the impact of vaping on offspring due to variability in ENDS usage amongst pregnant women [103]. Li et al. exposed mice to either air or cigarette smoke from six weeks before pregnancy until lactation. At mating, a subset of the mice exposed to CS were then shifted over to e-vapor exposure. The mice exposed to cigarette smoke for the entire duration had offspring with impaired glucose tolerance, increased plasma non-esterified fatty acids and liver triglyceride concentrations [104]. The offspring born to mice that had EC exposure upon mating did not improve glucose tolerance; however, these offspring did have reduced toxicity in pregnancy and reduced hepatic lipid metabolism [104]. Female Balb/c mice exposed to e-vapor, with and without nicotine, for six weeks before mating showed detrimental changes along with their offspring [104]. The offspring exposed to nicotine-free vapor had metabolic changes and liver damage, while those exposed to nicotine vapor had liver steatosis [104]. Nicotine and e-cigarette condensate have been shown to disrupt mitochondria by inhibiting OXPHOS complex III and increasing mtROS [105]. This increased mitochondrial dysregulation in redox signaling was ensued by inhibition of myofibroblast differentiation critical for proper development in HLF-1, which further impaired wound healing [105]. A previous assessment of in vitro and animal models highlighted the multifaceted mechanisms through which ENDS impacted pre and postnatal brain development [106]. Zahedi et al. demonstrated that the mechanism behind only EC with low or zero nicotine levels in EC -induced stem cell toxicity is stress-induced mitochondrial hyperfusion (SIMH), resulting in transitory survival, followed by increasing mitochondrial oxidative stress [107]. SIMH is identified as a survival response to nicotine and is largely present in EC refill fluids called do-it-yourself EC products [107]. They also observed that a high nicotine concentration (110 μg/mL) with EC caused a rapid influx of calcium. EC leads to cellular stress, diminishes cellular health in the stem cell population, elevates cellular aging, and develops mitochondriopathies [107]. We illustrated the EC effect on mitochondrial function in Figure 3. The susceptibility of stem cells, specifically neural stem cells, is essential to consider during embryonic development. Compared to adult lung cells, embryonic and neonatal cells were more sensitive to EC refill fluids [108]. This sensitivity was correlated to the number and concentration of chemicals used to flavor the refill fluids [108]. Since ENDS are marketed as a “safer” alternative to cigarettes, the connection between chemicals used for flavoring and cytotoxicity is worth paying attention to as these refill fluids are not currently regulated and have not been fully assessed for their effects. Behar et al. narrowed down cinnamaldehyde (CAD) and 2-methoxycinnamaldehyde (2MOCA) as highly cytotoxic to human embryonic stem cells [109]. These were two of the most toxic ingredients found within cinnamon-flavored EC refill fluids. The identification of toxicants in different flavors across different manufacturing companies is lacking. However, to fully understand the impact ENDS could have on fetal development and offspring health, this is an area of research that must be expanded. Maternal vaping during pregnancy may not be as extensively studied as maternal smoking during pregnancy but is a critical and imperative area to be considered when designing further studies.

5. Thirdhand Smoke

While the health impacts of thirdhand cigarette smoke (THS) are still being studied, it is undeniably a crucial component of addressing public and environmental health. Although experiments on the hazardous nature of THS are limited, an emerging set of data provide reasons not to exclude THS from future studies assessing risk factors. THS has been shown to cause stress-induced mitochondrial hyperfusion (SIMH) in mouse neural stem cells along with increased mitochondrial membrane potential (MMP), increased ATP levels, increased superoxide production, and increased oxidation of mitochondrial proteins [110]. SIMH can also dysregulate gene regulation, and transcription has been shown to reduce mitochondrial fission protein Fis1 expression [110], Figure 4 In Vivo exposure to THS increased AST, urea, and nuclear respiratory factor-1 (NRF1) levels in a time-dependent manner leading to increased liver dysfunction and mitochondrial dysfunction within the liver [111]. THS exposure has been shown to reduce the liver’s antioxidant potential in a time-dependent manner. This reduction in liver function was seen with some key changes, such as increased oxidative stress, reduced ATP levels, and increased lactate, indicating mitochondrial dysfunction within the liver [111]. Adhami et al. proposed that the connection between the dysfunctional changes was due to significantly higher TNF-α levels, which could play a role in mitochondrial dysfunction, given the cytokine’s role in many inflammatory and cell death pathways [111].
Pozuelos et al. conducted a randomized control trial to demonstrate how the acute inhalation of THS increased oxidative stress, mitochondrial membrane potential, ATP production, and decreased permeability of transition of mitochondria and mitochondrial membranes. These changes were accompanied by stress-induced mitochondrial hyperfusion and dysfunction and increased DNA repair mechanisms [79,112]. Stem cells exposed to THS also showed an increase in SIMH, but upon prolonged exposure, both mitochondrial membrane potential and cell proliferation decreased, ultimately leading to apoptosis of the cell [110].
To summarize, cigarette smoke and e-cigarette vapor are culprits causing many devastating and fatal diseases. Although tobacco smoking increases the risk of contracting diseases, psychological and social factors play a key role in maintaining the habit [113]. With an ever-present concern for this public health crisis, toxins in tobacco smoke have an undeniably detrimental effect on mitochondrial health further aggravating the pathophysiological mechanisms of different diseases. Understanding these mechanisms can be helpful in the development of therapeutics. For example, iPSC-MSCs reduced airway inflammation and offered protection against CS-induced mitochondrial oxidative stress, dysfunction, and apoptosis in human ASMCs and mouse lungs [114].

6. Conclusions

This review highlights how mitochondrial damage caused by inhaled intoxicants increases ROS production, apoptosis, reduces respiration, alters mitochondrial membrane potential, and destroys the equilibrium of fission/fusion effects. These detrimental changes contribute to aggravated inflammatory pathways and various disease pathogeneses. Mitochondrial damage responses to smoke vary in tissue-dependent and concentration-dependent manners, which indicate a need to develop specific studies on understanding the diverse effects and mechanisms which contribute to each unfolding disease process. Understanding these mechanisms can aid in the development of effective interventional and therapeutic modalities.
Furthermore, mitochondrial morphology and health are maintained by the dynamic opposing forces of mitochondrial fusion and fission, which are altered by means of various mechanisms involving increased mtROS, increased ATP, dysregulation of key proteins, and stress-induced mitochondrial hyperfusion. The intimate connection between mitochondrial morphological changes and dysfunction impairs multiple pathways and alters downstream signaling. Interestingly, these toxic changes vary based on the chemical composition of different e-liquids. The cell type also may impact which changes occur first and how mitochondria can behave differently in acute versus long-term exposure. Another factor influencing organelle behavior is exposure type and whether or not the exposure was direct or through second or thirdhand smoke. Therefore, further research on the cytotoxicity of aldehyde flavors available for ENDS users is crucial to developing public health guidelines to elucidate specific pathophysiological mechanisms. Although ENDS devices are offered as healthier alternatives to cigarette smoking, it is clear that they are not without risks, especially when concerning maternal health.

Author Contributions

Conceptualization: B.C. and G.U. Writing manuscript, M.K., S.J., S.I.S., A.M.R., G.U. and B.C. All authors have read and agreed to the published version of the manuscript.


This research was funded by NIH-R01 (AG053988) to G.U.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. WHO. Tobacco. 2020. Available online: (accessed on 17 April 2022).
  2. WHO. Electronic Nicotine and Non-Nicotine Delivery Systems: A Brief. 2020. Available online: (accessed on 17 April 2022).
  3. Grana, R.; Benowitz, N.; Glantz, S.A. E-cigarettes: A scientific review. Circulation 2014, 129, 1972–1986. [Google Scholar] [CrossRef] [PubMed]
  4. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco Smoke and Involuntary Smoking; IARC Monographs on the Evaluation of Carcinogenic Risks to Humans; IARC: Lyon, France, 2004; Volume 83.
  5. Jassem, E.; Szymanowska, A.; Siemińska, A.; Jassem, J. Smoking and lung cancer. Pneumonol. Alergol. Pol. 2009, 77, 469–473. [Google Scholar] [PubMed]
  6. Loeb, L.A.; Ernster, V.L.; Warner, K.E.; Abbotts, J.; Laszlo, J. Smoking and lung cancer: An overview. Cancer Res. 1984, 44, 5940–5958. [Google Scholar] [PubMed]
  7. Macacu, A.; Autier, P.; Boniol, M.; Boyle, P. Active and passive smoking and risk of breast cancer: A meta-analysis. Breast Cancer Res. Treat. 2015, 154, 213–224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Ambrose, J.A.; Barua, R.S. The pathophysiology of cigarette smoking and cardiovascular disease: An update. J. Am. Coll. Cardiol. 2004, 43, 1731–1737. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Leone, A.; Giannini, D.; Bellotto, C.; Balbarini, A. Passive smoking and coronary heart disease. Curr. Vasc. Pharm. 2004, 2, 175–182. [Google Scholar] [CrossRef]
  10. Rigotti, N.A.; Pasternak, R.C. Cigarette smoking and coronary heart disease: Risks and management. Cardiol. Clin. 1996, 14, 51–68. [Google Scholar] [CrossRef]
  11. Pan, B.; Jin, X.; Jun, L.; Qiu, S.; Zheng, Q.; Pan, M. The relationship between smoking and stroke: A meta-analysis. Medicine 2019, 98, e14872. [Google Scholar] [CrossRef]
  12. Shah, R.S.; Cole, J.W. Smoking and stroke: The more you smoke the more you stroke. Expert Rev. Cardiovasc. Ther. 2010, 8, 917–932. [Google Scholar] [CrossRef]
  13. Li, G.; Saad, S.; Oliver, B.G.; Chen, H. Heat or Burn? Impacts of Intrauterine Tobacco Smoke and E-Cigarette Vapor Exposure on the Offspring’s Health Outcome. Toxics 2018, 6, 43. [Google Scholar] [CrossRef] [Green Version]
  14. Arcavi, L.; Benowitz, N.L. Cigarette Smoking and Infection. Arch. Intern. Med. 2004, 164, 2206–2216. [Google Scholar] [CrossRef] [PubMed]
  15. Chan, Y.L.; Oliver, B.G.; Chen, H. What lessons have we learnt about the impact of maternal cigarette smoking from animal models? Clin. Exp. Pharmacol. Physiol. 2020, 47, 337–344. [Google Scholar] [CrossRef] [PubMed]
  16. Talhout, R.; Schulz, T.; Florek, E.; van Benthem, J.; Wester, P.; Opperhuizen, A. Hazardous compounds in tobacco smoke. Int. J. Environ. Res. Public Health 2011, 8, 613–628. [Google Scholar] [CrossRef] [PubMed]
  17. Konstantinou, E.; Fotopoulou, F.; Drosos, A.; Dimakopoulou, N.; Zagoriti, Z.; Niarchos, A.; Makrynioti, D.; Kouretas, D.; Farsalinos, K.; Lagoumintzis, G.; et al. Tobacco-specific nitrosamines: A literature review. Food Chem. Toxicol. 2018, 118, 198–203. [Google Scholar] [CrossRef]
  18. Hang, B.; Sarker, A.H.; Havel, C.; Saha, S.; Hazra, T.K.; Schick, S.; Jacob, P., 3rd; Rehan, V.K.; Chenna, A.; Sharan, D.; et al. Thirdhand smoke causes DNA damage in human cells. Mutagenesis 2013, 28, 381–391. [Google Scholar] [CrossRef]
  19. Kim, S.; Oancea, S.C. Electronic cigarettes may not be a “safer alternative” of conventional cigarettes during pregnancy: Evidence from the nationally representative PRAMS data. BMC Pregnancy Childbirth 2020, 20, 557. [Google Scholar] [CrossRef]
  20. Collins, L.; Glasser, A.M.; Abudayyeh, H.; Pearson, J.L.; Villanti, A.C. E-Cigarette Marketing and Communication: How E-Cigarette Companies Market E-Cigarettes and the Public Engages with E-cigarette Information. Nicotine Tob. Res. 2019, 21, 14–24. [Google Scholar] [CrossRef]
  21. Margham, J.; McAdam, K.; Forster, M.; Liu, C.; Wright, C.; Mariner, D.; Proctor, C. Chemical Composition of Aerosol from an E-Cigarette: A Quantitative Comparison with Cigarette Smoke. Chem. Res. Toxicol. 2016, 29, 1662–1678. [Google Scholar] [CrossRef]
  22. Spindel, E.R.; McEvoy, C.T. The Role of Nicotine in the Effects of Maternal Smoking during Pregnancy on Lung Development and Childhood Respiratory Disease. Implications for Dangers of E-Cigarettes. Am. J. Respir. Crit. Care Med. 2016, 193, 486–494. [Google Scholar] [CrossRef] [Green Version]
  23. Franzen, K.F.; Willig, J.; Cayo Talavera, S.; Meusel, M.; Sayk, F.; Reppel, M.; Dalhoff, K.; Mortensen, K.; Droemann, D. E-cigarettes and cigarettes worsen peripheral and central hemodynamics as well as arterial stiffness: A randomized, double-blinded pilot study. Vasc. Med. 2018, 23, 419–425. [Google Scholar] [CrossRef]
  24. Fetterman, J.L.; Hamburg, N.M. A cautionary note on electronic cigarettes and vascular health. Vasc. Med. 2018, 23, 426–427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Thirión-Romero, I.; Pérez-Padilla, R.; Zabert, G.; Barrientos-Gutiérrez, I. Respiratory impact of electronic cigarettes and “low-risk” tobacco. Rev. Investig. Clin. 2019, 71, 17–27. [Google Scholar] [CrossRef] [PubMed]
  26. Ralho, A.; Coelho, A.; Ribeiro, M.; Paula, A.; Amaro, I.; Sousa, J.; Marto, C.; Ferreira, M.; Carrilho, E. Effects of Electronic Cigarettes on Oral Cavity: A Systematic Review. J. Evid. Based Dent. Pract. 2019, 19, 101318. [Google Scholar] [CrossRef] [PubMed]
  27. Collins, Y.; Chouchani, E.T.; James, A.M.; Menger, K.E.; Cochemé, H.M.; Murphy, M.P. Mitochondrial redox signalling at a glance. J. Cell Sci. 2012, 125, 801–806. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Meyer, J.N.; Leung, M.C.; Rooney, J.P.; Sendoel, A.; Hengartner, M.O.; Kisby, G.E.; Bess, A.S. Mitochondria as a target of environmental toxicants. Toxicol. Sci. 2013, 134, 1–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Youle, R.J.; van der Bliek, A.M. Mitochondrial fission, fusion, and stress. Science 2012, 337, 1062–1065. [Google Scholar] [CrossRef] [Green Version]
  30. Jia, L.; Liu, Z.; Sun, L.; Miller, S.S.; Ames, B.N.; Cotman, C.W.; Liu, J. Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: Protection by (R)-alpha-lipoic acid. Investig. Ophthalmol. Vis. Sci. 2007, 48, 339–348. [Google Scholar] [CrossRef] [Green Version]
  31. Stridh, H.; Orrenius, S.; Hampton, M.B. Caspase Involvement in the Induction of Apoptosis by the Environmental Toxicants Tributyltin and Triphenyltin. Toxicol. Appl. Pharmacol. 1999, 156, 141–146. [Google Scholar] [CrossRef]
  32. Tsubouchi, K.; Araya, J.; Kuwano, K. PINK1-PARK2-mediated mitophagy in COPD and IPF pathogeneses. Inflamm. Regen. 2018, 38, 18. [Google Scholar] [CrossRef]
  33. Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795. [Google Scholar] [CrossRef]
  34. Wei, P.Z.; Szeto, C.C. Mitochondrial dysfunction in diabetic kidney disease. Clin. Chim. Acta 2019, 496, 108–116. [Google Scholar] [CrossRef] [PubMed]
  35. Srinivasan, S.; Guha, M.; Kashina, A.; Avadhani, N.G. Mitochondrial dysfunction and mitochondrial dynamics—The cancer connection. Biochim. Biophys. Acta Bioenerg. 2017, 1858, 602–614. [Google Scholar] [CrossRef] [PubMed]
  36. West, A.P. Mitochondrial dysfunction as a trigger of innate immune responses and inflammation. Toxicology 2017, 391, 54–63. [Google Scholar] [CrossRef]
  37. El-Hattab, A.W.; Craigen, W.J.; Scaglia, F. Mitochondrial DNA maintenance defects. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 1539–1555. [Google Scholar] [CrossRef] [PubMed]
  38. Yan, C.; Duanmu, X.; Zeng, L.; Liu, B.; Song, Z. Mitochondrial DNA: Distribution, Mutations, and Elimination. Cells 2019, 8, 379. [Google Scholar] [CrossRef] [Green Version]
  39. Zanna, C.; Ghelli, A.; Porcelli, A.M.; Karbowski, M.; Youle, R.J.; Schimpf, S.; Wissinger, B.; Pinti, M.; Cossarizza, A.; Vidoni, S.; et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 2007, 131, 352–367. [Google Scholar] [CrossRef] [Green Version]
  40. Sweeney, M.G.; Bundey, S.; Brockington, M.; Poulton, K.R.; Winer, J.B.; Harding, A.E. Mitochondrial myopathy associated with sudden death in young adults and a novel mutation in the mitochondrial DNA leucine transfer RNA(UUR) gene. QJM 1993, 86, 709–713. [Google Scholar]
  41. Gerbitz, K.D.; Gempel, K.; Brdiczka, D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 1996, 45, 113–126. [Google Scholar] [CrossRef]
  42. Venditti, P.; Di Stefano, L.; Di Meo, S. Mitochondrial metabolism of reactive oxygen species. Mitochondrion 2013, 13, 71–82. [Google Scholar] [CrossRef]
  43. Mishra, P.; Chan, D.C. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat. Rev. Mol. Cell Biol. 2014, 15, 634–646. [Google Scholar] [CrossRef] [Green Version]
  44. Nunnari, J.; Suomalainen, A. Mitochondria: In sickness and in health. Cell 2012, 148, 1145–1159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Annesley, S.J.; Fisher, P.R. Mitochondria in Health and Disease. Cells 2019, 8, 680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Archer, S.L. Mitochondrial fission and fusion in human diseases. N. Engl. J. Med. 2014, 370, 1074. [Google Scholar] [CrossRef] [PubMed]
  47. Otera, H.; Ishihara, N.; Mihara, K. New insights into the function and regulation of mitochondrial fission. Biochim. Biophys. Acta 2013, 1833, 1256–1268. [Google Scholar] [CrossRef] [Green Version]
  48. Detmer, S.A.; Chan, D.C. Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 2007, 8, 870–879. [Google Scholar] [CrossRef]
  49. Yoon, Y.; Galloway, C.A.; Jhun, B.S.; Yu, T. Mitochondrial dynamics in diabetes. Antioxid. Redox Signal. 2011, 14, 439–457. [Google Scholar] [CrossRef]
  50. Olichon, A.; Guillou, E.; Delettre, C.; Landes, T.; Arnauné-Pelloquin, L.; Emorine, L.J.; Mils, V.; Daloyau, M.; Hamel, C.; Amati-Bonneau, P.; et al. Mitochondrial dynamics and disease, OPA1. Biochim. Biophys. Acta (BBA)-Mol. Cell Res. 2006, 1763, 500–509. [Google Scholar] [CrossRef] [Green Version]
  51. Chen, H.; Chan, D.C. Mitochondrial dynamics--fusion, fission, movement, and mitophagy—In neurodegenerative diseases. Hum. Mol. Genet. 2009, 18, R169–R176. [Google Scholar] [CrossRef]
  52. Wakabayashi, J.; Zhang, Z.; Wakabayashi, N.; Tamura, Y.; Fukaya, M.; Kensler, T.W.; Iijima, M.; Sesaki, H. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell Biol. 2009, 186, 805–816. [Google Scholar] [CrossRef] [Green Version]
  53. Chen, H.; Detmer, S.A.; Ewald, A.J.; Griffin, E.E.; Fraser, S.E.; Chan, D.C. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 2003, 160, 189–200. [Google Scholar] [CrossRef]
  54. Shen, Q.; Yamano, K.; Head, B.P.; Kawajiri, S.; Cheung, J.T.; Wang, C.; Cho, J.H.; Hattori, N.; Youle, R.J.; van der Bliek, A.M. Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol. Biol. Cell 2014, 25, 145–159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Chen, H.; Vermulst, M.; Wang, Y.E.; Chomyn, A.; Prolla, T.A.; McCaffery, J.M.; Chan, D.C. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 2010, 141, 280–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Palmer, C.S.; Osellame, L.D.; Laine, D.; Koutsopoulos, O.S.; Frazier, A.E.; Ryan, M.T. MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep. 2011, 12, 565–573. [Google Scholar] [CrossRef] [PubMed]
  57. Zhang, Z.; Liu, L.; Wu, S.; Xing, D. Drp1, Mff, Fis1, and MiD51 are coordinated to mediate mitochondrial fission during UV irradiation-induced apoptosis. FASEB J. 2016, 30, 466–476. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Eura, Y.; Ishihara, N.; Oka, T.; Mihara, K. Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function. J. Cell Sci. 2006, 119, 4913–4925. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Aravamudan, B.; Kiel, A.; Freeman, M.; Delmotte, P.; Thompson, M.; Vassallo, R.; Sieck, G.C.; Pabelick, C.M.; Prakash, Y.S. Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 306, L840–L854. [Google Scholar] [CrossRef] [Green Version]
  60. Song, Z.; Chen, H.; Fiket, M.; Alexander, C.; Chan, D.C. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J. Cell Biol. 2007, 178, 749–755. [Google Scholar] [CrossRef]
  61. Zhang, Y.; Liu, Q.; Li, Y.; Li, C.; Zhu, Y.; Xia, F.; Xu, S.; Li, W. PTEN-Induced Putative Kinase 1 (PINK1)/Parkin-Mediated Mitophagy Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity. Med. Sci. Monit. 2019, 25, 8797–8806. [Google Scholar] [CrossRef]
  62. Wang, N.; Zhu, P.; Huang, R.; Wang, C.; Sun, L.; Lan, B.; He, Y.; Zhao, H.; Gao, Y. PINK1: The guard of mitochondria. Life Sci. 2020, 259, 118247. [Google Scholar] [CrossRef]
  63. Quinn, P.M.J.; Moreira, P.I.; Ambrósio, A.F.; Alves, C.H. PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta Neuropathol. Commun. 2020, 8, 189. [Google Scholar] [CrossRef]
  64. Pickles, S.; Vigié, P.; Youle, R.J. Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance. Curr. Biol. 2018, 28, R170–R185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Lazarou, M. Keeping the immune system in check: A role for mitophagy. Immunol. Cell Biol. 2015, 93, 3–10. [Google Scholar] [CrossRef] [PubMed]
  66. Cai, Q.; Jeong, Y.Y. Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases. Cells 2020, 9, 150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Bravo-San Pedro, J.M.; Kroemer, G.; Galluzzi, L. Autophagy and Mitophagy in Cardiovascular Disease. Circ. Res. 2017, 120, 1812–1824. [Google Scholar] [CrossRef]
  68. Killackey, S.A.; Philpott, D.J.; Girardin, S.E. Mitophagy pathways in health and disease. J. Cell Biol. 2020, 219, e202004029. [Google Scholar] [CrossRef]
  69. Teague, S.V.; Pinkerton, K.E.; Goldsmith, M.; Gebremichael, A.; Chang, S.; Jenkins, R.A.; Moneyhun, J.H. Sidestream Cigarette Smoke Generation and Exposure System for Environmental Tobacco Smoke Studies. Inhal. Toxicol. 1994, 6, 79–93. [Google Scholar] [CrossRef]
  70. Abouassali, O.; Chang, M.; Chidipi, B.; Martinez, J.L.; Reiser, M.; Kanithi, M.; Soni, R.; McDonald, T.V.; Herweg, B.; Saiz, J.; et al. In vitro and in vivo cardiac toxicity of flavored electronic nicotine delivery systems. Am. J. Physiol. Heart Circ. Physiol. 2021, 320, H133–H143. [Google Scholar] [CrossRef]
  71. Hamanaka, R.B.; Chandel, N.S. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem. Sci. 2010, 35, 505–513. [Google Scholar] [CrossRef] [Green Version]
  72. Kussmaul, L.; Hirst, J. The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc. Natl. Acad. Sci. USA 2006, 103, 7607–7612. [Google Scholar] [CrossRef] [Green Version]
  73. Pryde, K.R.; Hirst, J. Superoxide is produced by the reduced flavin in mitochondrial complex I: A single, unified mechanism that applies during both forward and reverse electron transfer. J. Biol. Chem. 2011, 286, 18056–18065. [Google Scholar] [CrossRef] [Green Version]
  74. Kudin, A.P.; Bimpong-Buta, N.Y.; Vielhaber, S.; Elger, C.E.; Kunz, W.S. Characterization of superoxide-producing sites in isolated brain mitochondria. J. Biol. Chem. 2004, 279, 4127–4135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Qin, Y.; Liu, Y.; Jiang, Y.; Mei, S.; Liu, Y.; Feng, J.; Guo, L.; Du, J.; Graves, D.T.; Liu, Y. Cigarette Smoke Exposure Inhibits Osteoclast Apoptosis via the mtROS Pathway. J. Dent. Res. 2021, 100, 1378–1386. [Google Scholar] [CrossRef] [PubMed]
  76. Sundar, I.K.; Maremanda, K.P.; Rahman, I. Mitochondrial dysfunction is associated with Miro1 reduction in lung epithelial cells by cigarette smoke. Toxicol. Lett. 2019, 317, 92–101. [Google Scholar] [CrossRef]
  77. Manevski, M.; Muthumalage, T.; Devadoss, D.; Sundar, I.K.; Wang, Q.; Singh, K.P.; Unwalla, H.J.; Chand, H.S.; Rahman, I. Cellular stress responses and dysfunctional Mitochondrial-cellular senescence, and therapeutics in chronic respiratory diseases. Redox Biol. 2020, 33, 101443. [Google Scholar] [CrossRef]
  78. Wang, Z.; White, A.; Wang, X.; Ko, J.; Choudhary, G.; Lange, T.; Rounds, S.; Lu, Q. Mitochondrial Fission Mediated Cigarette Smoke-induced Pulmonary Endothelial Injury. Am. J. Respir. Cell Mol. Biol. 2020, 63, 637–651. [Google Scholar] [CrossRef]
  79. Pozuelos, G.L.; Kagda, M.S.; Schick, S.; Girke, T.; Volz, D.C.; Talbot, P. Experimental Acute Exposure to Thirdhand Smoke and Changes in the Human Nasal Epithelial Transcriptome: A Randomized Clinical Trial. JAMA Netw. Open 2019, 2, e196362. [Google Scholar] [CrossRef] [Green Version]
  80. Tan, D.; Goerlitz, D.S.; Dumitrescu, R.G.; Han, D.; Seillier-Moiseiwitsch, F.; Spernak, S.M.; Orden, R.A.; Chen, J.; Goldman, R.; Shields, P.G. Associations between cigarette smoking and mitochondrial DNA abnormalities in buccal cells. Carcinogenesis 2008, 29, 1170–1177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Baglole, C.J.; Bushinsky, S.M.; Garcia, T.M.; Kode, A.; Rahman, I.; Sime, P.J.; Phipps, R.P. Differential induction of apoptosis by cigarette smoke extract in primary human lung fibroblast strains: Implications for emphysema. Am. J. Physiol. Lung Cell Mol. Physiol. 2006, 291, L19–L29. [Google Scholar] [CrossRef] [Green Version]
  82. van der Toorn, M.; Rezayat, D.; Kauffman, H.F.; Bakker, S.J.; Gans, R.O.; Koëter, G.H.; Choi, A.M.; van Oosterhout, A.J.; Slebos, D.J. Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2009, 297, L109–L114. [Google Scholar] [CrossRef] [Green Version]
  83. Ballweg, K.; Mutze, K.; Königshoff, M.; Eickelberg, O.; Meiners, S. Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 307, L895–L907. [Google Scholar] [CrossRef]
  84. Hara, H.; Araya, J.; Ito, S.; Kobayashi, K.; Takasaka, N.; Yoshii, Y.; Wakui, H.; Kojima, J.; Shimizu, K.; Numata, T.; et al. Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2013, 305, L737–L746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Park, E.J.; Park, Y.J.; Lee, S.J.; Lee, K.; Yoon, C. Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells. Toxicol. Lett. 2019, 303, 55–66. [Google Scholar] [CrossRef] [PubMed]
  86. Hoffmann, R.F.; Zarrintan, S.; Brandenburg, S.M.; Kol, A.; de Bruin, H.G.; Jafari, S.; Dijk, F.; Kalicharan, D.; Kelders, M.; Gosker, H.R.; et al. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 2013, 14, 97. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Williams, M.A.; Reddy, G.; Quinn, M.J.; Millikan Bell, A. Toxicological assessment of electronic cigarette vaping: An emerging threat to force health, readiness and resilience in the U.S. Army. Drug Chem. Toxicol. 2021, 1–37. [Google Scholar] [CrossRef] [PubMed]
  88. Godoy, J.A.; Valdivieso, A.G.; Inestrosa, N.C. Nicotine Modulates Mitochondrial Dynamics in Hippocampal Neurons. Mol. Neurobiol. 2018, 55, 8965–8977. [Google Scholar] [CrossRef]
  89. Guo, L.; Li, L.; Wang, W.; Pan, Z.; Zhou, Q.; Wu, Z. Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells. Biochim. Biophys. Acta 2012, 1822, 852–861. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Chernyavsky, A.I.; Shchepotin, I.B.; Galitovkiy, V.; Grando, S.A. Mechanisms of tumor-promoting activities of nicotine in lung cancer: Synergistic effects of cell membrane and mitochondrial nicotinic acetylcholine receptors. BMC Cancer 2015, 15, 152. [Google Scholar] [CrossRef] [Green Version]
  91. Bruin, J.E.; Petre, M.A.; Lehman, M.A.; Raha, S.; Gerstein, H.C.; Morrison, K.M.; Holloway, A.C. Maternal nicotine exposure increases oxidative stress in the offspring. Free Radic. Biol. Med. 2008, 44, 1919–1925. [Google Scholar] [CrossRef]
  92. Hirata, N.; Yamada, S.; Asanagi, M.; Sekino, Y.; Kanda, Y. Nicotine induces mitochondrial fission through mitofusin degradation in human multipotent embryonic carcinoma cells. Biochem. Biophys. Res. Commun. 2016, 470, 300–305. [Google Scholar] [CrossRef]
  93. Picca, A.; Mankowski, R.T.; Burman, J.L.; Donisi, L.; Kim, J.S.; Marzetti, E.; Leeuwenburgh, C. Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat. Rev. Cardiol. 2018, 15, 543–554. [Google Scholar] [CrossRef]
  94. Zhu, S.H.; Sun, J.Y.; Bonnevie, E.; Cummins, S.E.; Gamst, A.; Yin, L.; Lee, M. Four hundred and sixty brands of e-cigarettes and counting: Implications for product regulation. Tob. Control 2014, 23 (Suppl. 3), iii3–iii9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Leigh, N.J.; Lawton, R.I.; Hershberger, P.A.; Goniewicz, M.L. Flavourings significantly affect inhalation toxicity of aerosol generated from electronic nicotine delivery systems (ENDS). Tob. Control 2016, 25, ii81–ii87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Cooper, S.Y.; Akers, A.T.; Henderson, B.J. Flavors Enhance Nicotine Vapor Self-administration in Male Mice. Nicotine Tob. Res. 2021, 23, 566–572. [Google Scholar] [CrossRef] [PubMed]
  97. Avelar, A.J.; Akers, A.T.; Baumgard, Z.J.; Cooper, S.Y.; Casinelli, G.P.; Henderson, B.J. Why flavored vape products may be attractive: Green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function. Neuropharmacology 2019, 158, 107729. [Google Scholar] [CrossRef] [PubMed]
  98. Basma, H.; Tatineni, S.; Dhar, K.; Qiu, F.; Rennard, S.; Lowes, B.D. Electronic cigarette extract induced toxic effect in iPS-derived cardiomyocytes. BMC Cardiovasc. Disord. 2020, 20, 357. [Google Scholar] [CrossRef]
  99. Jabba, S.V.; Diaz, A.N.; Erythropel, H.C.; Zimmerman, J.B.; Jordt, S.-E. Chemical Adducts of Reactive Flavor Aldehydes Formed in E-Cigarette Liquids Are Cytotoxic and Inhibit Mitochondrial Function in Respiratory Epithelial Cells. Nicotine Tob. Res. 2020, 22, S25–S34. [Google Scholar] [CrossRef]
  100. Williams, M.; Ventura, J.; Loza, A.; Wang, Y.; Talbot, P. Chemical Elements in Electronic Cigarette Solvents and Aerosols Inhibit Mitochondrial Reductases and Induce Oxidative Stress. Nicotine Tob. Res. 2020, 22, S14–S24. [Google Scholar] [CrossRef]
  101. Zhao, D.; Aravindakshan, A.; Hilpert, M.; Olmedo, P.; Rule, A.M.; Navas-Acien, A.; Aherrera, A. Metal/Metalloid Levels in Electronic Cigarette Liquids, Aerosols, and Human Biosamples: A Systematic Review. Environ. Health Perspect. 2020, 128, 36001. [Google Scholar] [CrossRef] [Green Version]
  102. Northrup, T.F.; Klawans, M.R.; Villarreal, Y.R.; Abramovici, A.; Suter, M.A.; Mastrobattista, J.M.; Moreno, C.A.; Aagaard, K.M.; Stotts, A.L. Family Physicians’ Perceived Prevalence, Safety, and Screening for Cigarettes, Marijuana, and Electronic-Nicotine Delivery Systems (ENDS) Use during Pregnancy. J. Am. Board Fam. Med. 2017, 30, 743–757. [Google Scholar] [CrossRef] [Green Version]
  103. Calder, R.; Gant, E.; Bauld, L.; McNeill, A.; Robson, D.; Brose, L.S. Vaping in Pregnancy: A Systematic Review. Nicotine Tob. Res. 2021, 23, 1451–1458. [Google Scholar] [CrossRef]
  104. Li, G.; Chan, Y.L.; Wang, B.; Saad, S.; George, J.; Oliver, B.G.; Chen, H. E-cigarettes damage the liver and alter nutrient metabolism in pregnant mice and their offspring. Ann. N. Y. Acad. Sci. 2020, 1475, 64–77. [Google Scholar] [CrossRef] [PubMed]
  105. Lei, W.; Lerner, C.; Sundar, I.K.; Rahman, I. Myofibroblast differentiation and its functional properties are inhibited by nicotine and e-cigarette via mitochondrial OXPHOS complex III. Sci. Rep. 2017, 7, 43213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Sailer, S.; Sebastiani, G.; Andreu-Férnández, V.; García-Algar, O. Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development. Int. J. Environ. Res. Public Health 2019, 16, 5113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Zahedi, A.; Phandthong, R.; Chaili, A.; Leung, S.; Omaiye, E.; Talbot, P. Mitochondrial Stress Response in Neural Stem Cells Exposed to Electronic Cigarettes. iScience 2019, 16, 250–269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Bahl, V.; Lin, S.; Xu, N.; Davis, B.; Wang, Y.H.; Talbot, P. Comparison of electronic cigarette refill fluid cytotoxicity using embryonic and adult models. Reprod. Toxicol. 2012, 34, 529–537. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Behar, R.Z.; Davis, B.; Wang, Y.; Bahl, V.; Lin, S.; Talbot, P. Identification of toxicants in cinnamon-flavored electronic cigarette refill fluids. Toxicol. In Vitro 2014, 28, 198–208. [Google Scholar] [CrossRef] [Green Version]
  110. Bahl, V.; Johnson, K.; Phandthong, R.; Zahedi, A.; Schick, S.F.; Talbot, P. From the Cover: Thirdhand Cigarette Smoke Causes Stress-Induced Mitochondrial Hyperfusion and Alters the Transcriptional Profile of Stem Cells. Toxicol. Sci. 2016, 153, 55–69. [Google Scholar] [CrossRef] [Green Version]
  111. Adhami, N.; Chen, Y.; Martins-Green, M. Biomarkers of disease can be detected in mice as early as 4 weeks after initiation of exposure to third-hand smoke levels equivalent to those found in homes of smokers. Clin. Sci. 2017, 131, 2409–2426. [Google Scholar] [CrossRef] [Green Version]
  112. Tondera, D.; Grandemange, S.; Jourdain, A.; Karbowski, M.; Mattenberger, Y.; Herzig, S.; Da Cruz, S.; Clerc, P.; Raschke, I.; Merkwirth, C.; et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 2009, 28, 1589–1600. [Google Scholar] [CrossRef] [Green Version]
  113. West, R. Tobacco smoking: Health impact, prevalence, correlates and interventions. Psychol. Health 2017, 32, 1018–1036. [Google Scholar] [CrossRef] [Green Version]
  114. Li, X.; Michaeloudes, C.; Zhang, Y.; Wiegman, C.H.; Adcock, I.M.; Lian, Q.; Mak, J.C.W.; Bhavsar, P.K.; Chung, K.F. Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways. J. Allergy Clin. Immunol. 2018, 141, 1634–1645.e1635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. Schematic cartoon of mitochondrial fusion and fission. Mitochondrial fusion occurs when two mitochondria fuse together, whereas fission occurs when one mitochondrion splits into two. Fusion is coordinated on the OMM by the mitofusins (MFN1 and MFN2), and on the IMM by optic atrophy 1 (OPA1). In fission, FIS1 and drp1 are largely involved.
Figure 1. Schematic cartoon of mitochondrial fusion and fission. Mitochondrial fusion occurs when two mitochondria fuse together, whereas fission occurs when one mitochondrion splits into two. Fusion is coordinated on the OMM by the mitofusins (MFN1 and MFN2), and on the IMM by optic atrophy 1 (OPA1). In fission, FIS1 and drp1 are largely involved.
Cells 11 01688 g001
Figure 2. Mitochondrial quality control pathways in healthy cells and CSE treated cells. (A). Mitochondrial biogenesis and network regulation rely on key transcription factors and various proteins to maintain the processes needed for the organelle’s homeostasis. Mitochondrial transcription factor A (TFAM) acts on mtDNA after being imported into mitochondria and is an essential transcription factor needed to encode mitochondrial proteins. The first of these proteins transcribed include electron transport chain subunits to increase and maintain the appropriate number of mitochondria to sustain oxygen consumption and ATP synthesis. Secondly, fusion proteins (MFN, MFN2, and OPA1) and fission proteins (Drp1 and FIS1) are transcribed to maintain healthy morphology by excising and clearing out damaged portions of the organelle. Mitophagy, a specialized autophagic pathway, eventually recycles the discarded mitochondrial components [93]. (B). In human airway smooth muscle, CS disrupts mitochondrial homeostasis by causing morphological changes and dysfunction. CS-induced mitochondrial fragmentation and damage to networked morphology occurs in a concentration-dependent fashion. CS also increased Drp1 expression, decreased Mfn2, and involved ROS. Furthermore, NF-κB and nuclear erythroid 2-related factor 2 (NRF2) lead to a transcriptional upregulation and increased activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and protein kinase C (PKC) [59].
Figure 2. Mitochondrial quality control pathways in healthy cells and CSE treated cells. (A). Mitochondrial biogenesis and network regulation rely on key transcription factors and various proteins to maintain the processes needed for the organelle’s homeostasis. Mitochondrial transcription factor A (TFAM) acts on mtDNA after being imported into mitochondria and is an essential transcription factor needed to encode mitochondrial proteins. The first of these proteins transcribed include electron transport chain subunits to increase and maintain the appropriate number of mitochondria to sustain oxygen consumption and ATP synthesis. Secondly, fusion proteins (MFN, MFN2, and OPA1) and fission proteins (Drp1 and FIS1) are transcribed to maintain healthy morphology by excising and clearing out damaged portions of the organelle. Mitophagy, a specialized autophagic pathway, eventually recycles the discarded mitochondrial components [93]. (B). In human airway smooth muscle, CS disrupts mitochondrial homeostasis by causing morphological changes and dysfunction. CS-induced mitochondrial fragmentation and damage to networked morphology occurs in a concentration-dependent fashion. CS also increased Drp1 expression, decreased Mfn2, and involved ROS. Furthermore, NF-κB and nuclear erythroid 2-related factor 2 (NRF2) lead to a transcriptional upregulation and increased activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and protein kinase C (PKC) [59].
Cells 11 01688 g002
Figure 3. The effects of EC vaping on mitochondrial function. EC vaping with high concertation of nicotine causes mitochondrial swelling associated with mitochondrial calcium overload and increases ROS. EC vaping with aerosols and low nicotine concentration causes mitochondrial hyperfusion associated with stress and elevates the ROS.
Figure 3. The effects of EC vaping on mitochondrial function. EC vaping with high concertation of nicotine causes mitochondrial swelling associated with mitochondrial calcium overload and increases ROS. EC vaping with aerosols and low nicotine concentration causes mitochondrial hyperfusion associated with stress and elevates the ROS.
Cells 11 01688 g003
Figure 4. The effect of THS on mitochondria and cell health. THS caused SIMH accompanied by decreased expression of mitochondrial fission protein Fis1 causes the elevation of ROS [110].
Figure 4. The effect of THS on mitochondria and cell health. THS caused SIMH accompanied by decreased expression of mitochondrial fission protein Fis1 causes the elevation of ROS [110].
Cells 11 01688 g004
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Kanithi, M.; Junapudi, S.; Shah, S.I.; Matta Reddy, A.; Ullah, G.; Chidipi, B. Alterations of Mitochondrial Network by Cigarette Smoking and E-Cigarette Vaping. Cells 2022, 11, 1688.

AMA Style

Kanithi M, Junapudi S, Shah SI, Matta Reddy A, Ullah G, Chidipi B. Alterations of Mitochondrial Network by Cigarette Smoking and E-Cigarette Vaping. Cells. 2022; 11(10):1688.

Chicago/Turabian Style

Kanithi, Manasa, Sunil Junapudi, Syed Islamuddin Shah, Alavala Matta Reddy, Ghanim Ullah, and Bojjibabu Chidipi. 2022. "Alterations of Mitochondrial Network by Cigarette Smoking and E-Cigarette Vaping" Cells 11, no. 10: 1688.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop