Dysfunctional mitochondria are highly related with pathogenesis of COPD that might via mitochondrial damage associate molecular patterns (DAMPS) from dying or stressed cells including enhanced ROS production, inflammation response as well as cellular senescence (Lerner et al., 2016; Brusselle et al., 2011). COPD shows increased oxidative stress, especially during acute outbreaks caused by the overproduction of ROS resulting from CS, air pollution, biomass smoke, inflammatory responses of lung infections, and mitochondrial stress (Noguera et al., 2001). Compared with a nonsmoker or a population that quit smoking for a long time, the bronchial epithelia from COPD patients showed enhanced mtROS and lower levels of manganese superoxide dismutase 2 (SOD2) (Haji et al., 2020). Decreased mitochondrial complexes and increased mtROS were noticed in the airway smooth muscular cells of COPD patients (Wiegman et al., 2015) (Figure 1A).

Mitochondrial deacetylase sirtuin 3 (SIRT3) is an upstream signaling factor that regulates mtROS homeostasis (Bause and Haigis, 2013). It can directly bind with and deacetylate mitochondrial antioxidant enzymes such as SOD2 (Tao et al., 2010), isocitrate dehydrogenase 2 (Yu et al., 2012), and glutathione peroxidase (Liu et al., 2015), resulting in the increased activity to regulate the mtROS level (Bause and Haigis, 2013). In contrast, the overexpression of SIRT3 leads to significant abolishing of trimethylamine N-oxide (TMAO)-induced SOD2 suppression and mtROS production (Zhang et al., 2017). The study suggested that curcumin might be involved in the upregulation of PGC-1α/SIRT3 signaling to attenuate impairing skeletal muscle mitochondria in COPD rats (Zhang et al., 2017). In addition, high-level SIRT3 can prevent SOD2 from decreasing and can also improve the mitochondrial oxidative stress of cigarette smoke extract (CSE)-treated airway epithelia, which suggests that SIRT3 might contribute to the suppression of COPD pathogenesis by inhibiting mitochondrial oxidative stress via the modification of SOD2 (Zhang et al., 2020). Another family member, namely, SIRT1, is involved in the regulation of mitochondrial oxidative stress gene expression, including NOX4 (Dasgupta et al., 2020) and SOD2 (Liu et al., 2019). SIRT1 overexpression can protect airway epithelia from CS-induced senescence by interacting with FOXO3; it suggests that modulating mitochondrial function might be a potential therapeutic strategy for COPD treatment (Yao et al., 2012; Aghapour et al., 2020).

mtDNA is susceptible to oxidative damage due to its proximity to ROS production sites, special packaging structures, and asymmetric replication (Reyes et al., 1998; Parisi and Clayton, 1991). Excessive mtROS results in mtDNA site mutations, insertions, deletions, and copy number reduction (Quan et al., 2020). Different types of damage to mtDNA can also occur because of endogenous and exogenous (tobacco smoke, chemicals, etc.) noxious substances (Alexeyev et al., 2013). Damaged mtDNA fragments can escape into the cytoplasm or extracellular space, which may be related to changes in mitochondrial permeability, mitochondrial dynamics, mitophagy, BAX/BAK pores, and VDAC1 oligomers (Pérez-Treviño et al., 2020). It has been reported that the mtDNA content does not change in end-stage COPD lung tissue, but the mtDNA strand breaks and/or untrustworthy sites are significantly increased compared with normal lung tissue (Pastukh et al., 2011). In a SPIROMICS cohort study (NCT01969344), higher levels of plasma-mtDNA were found in subjects with mild or moderate COPD than in nonsmokers and smokers without airflow obstruction (Zhang W. Z. et al., 2021). Similarly, plasma levels of both cell-free mtDNA (cf-mtDNA) and nuclear DNA (cf-nDNA) were elevated in former COPD smokers compared with that in former smokers without COPD (Giordano et al., 2022). Increased cf-mtDNA copy number was significantly associated with the development of COPD. They also found that bronchial epithelia exposed to CSE led to the release of mtDNA into the extracellular space through vehicles and cellular debris (Giordano et al., 2022).

The mtDNA released from mitochondria is considered a damage-associated molecular pattern (DAMP) by activating downstream pro-inflammatory signaling cascades (Fang et al., 2016). Activation of human polymorphonuclear neutrophils (PMNs) by mtDNA in the plasma through TLR9 induces secondary IL-8 release and activates PMN p38 and p44/42 MAPKs, leading to systemic inflammation (Zhang et al., 2010). Cytosolic mtDNA also mediates inflammatory responses in the intracellular space by contributing to IL-1β and IL-18 secretion through the activation of the NLRP3/AIM2-caspase-1 pathway (Nakahira et al., 2011). The accumulation of mtDNA activates cGAS-STING signaling and IFN-I responses in DCs, B cells, and natural killer cells (West and Shadel, 2017), resulting in enhanced inflammatory responses. In addition, damaged mtDNA can increase the expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and elevated PCSK9 can induce apoptosis by stimulating caspase-3 (Ding et al., 2016).

Mitochondrial dysfunction plays a central role in the aging process, and mtDNA mutations are critical hallmarks of cellular aging and other related diseases (Szczepanowska and Trifunovic, 2017; van der Rijt et al., 2020) (Figure 1B). As previously described, oxidatively damaged mtDNA results in reduced gene expression of mtDNA, defects in the oxidative phosphorylation system, and increased oxidative flux (Wallace, 1992); this is a common feature in many human aging tissues, including lung tissue (Bender et al., 2006). Studies have demonstrated that mtDNA drives cGAS-dependent responses and enhances senescence in lung epithelia and fibroblasts (Schuliga et al., 2021; Schuliga et al., 2020). mtDNA mutations also accelerate oocyte aging by reducing the NADH/NAD⁺ redox state (Yang et al., 2020). The accumulation of mtDNA damage has also been shown to promote apoptosis by increasing c-caspase-3 and Cyto c release and leading to mitochondrial outer membrane permeabilization (MOMP) (Kujoth et al., 2005). These studies suggest that drugs that protect mtDNA may have the potential effect of slowing COPD progression by affecting cellular senescence and inflammatory pathogenesis (Figure 1B).

Mitochondrial membrane potential (MMP/ΔΨm) plays an important role in maintaining mitochondrial function, mitochondrial permeability, mitochondrial viability, and other cellular functions (Bagkos et al., 2014; Gottlieb et al., 2003). It has been observed that CSE leads to the loss of cellular ATP and rapid depolarization of MMP (Wu et al., 2020). Reduced MMP/ΔΨm was noticed in mitochondria isolated from bronchial biopsies of COPD patients (Haji et al., 2020). Human airway smooth muscle cells from COPD patients have reduced MMP, ATP content, and basal and maximal respiration compared to those from healthy controls (Wiegman et al., 2015). Likewise, both MMP and ATP levels were significantly reduced in quadriceps muscle cells of CS-exposed rats compared to controls, which are associated with the decreased physical ability of COPD rats (Mao et al., 2019). Decreased or depolarized MMP is considered an important indicator of mitochondrial dysfunction, with profound effects on inflammatory responses and apoptosis (Zhou et al., 2021) (Figure 1C).

Disrupting MMP directly affects the electron transport chain (ETC) that in turn leads to loss of oxidative phosphorylation and increases mtROS production. Depolarized MMP induces a transition in mitochondrial membrane permeability that leads to the release of mtROS, mtDNA, and intermembrane proteins into the cytosol, resulting in triggering inflammatory and proapoptotic responses (Bronner and O'Riordan, 2016). Improving mitochondrial function and decreasing mtROS generation can attenuate inflammatory response (Chen Y. et al., 2023). Cleaved oxidized-mtDNA promotes NLRP3 inflammasome and cGAS-STING signaling activation, leading to the pathogenesis of chronic inflammatory diseases (Xian et al., 2022).

MMP reduction is a key event in the induction of apoptosis (Zaib et al., 2022). The pro-apoptotic Bcl-2 family protein BAK/BAX can regulate the MMP change; the activation and oligomerization of BAK/BAX can induce homomultimeric pores formation (Korsmeyer et al., 2000) or induce the MOMP (Kuwana et al., 2002). BAK/BAX can bind to and promote the opening of VDAC1, leading to decreasing MMP (Shimizu et al., 1999). The decline in MMP causes structural changes in mitochondria, including matrix condensation and cristae disintegration (Gottlieb et al., 2003). These structural changes result in the release of Cyto c into the intermembrane space and cytoplasm (Gottlieb et al., 2003). The released Cyto c results in apoptosis by activating Apaf-1-caspase-9 apoptosome and subsequently activating executioner caspase-3 (Yuan and Akey, 2013). The impact of abnormal MMP on the pathogenesis of COPD may be more complicated, and further research is needed.

Mitophagy-associated signals are highly related to the pathogenesis of COPD, such as AMPK signaling. Studies have shown that AMPK can directly phosphorylate the serine/threonine kinase ULK1 (Kim et al., 2011; Egan et al., 2011); then, ULK1 promotes mitophagy by promoting phosphorylation of the Parkin ACT domain (Hung et al., 2021). ULK1 can also directly phosphorylate mitophagy receptors, including FUNDC1 (Wu et al., 2014), BNIP3 (Poole et al., 2021), NIX, and Bcl-2-L-13 (Kim et al., 2011; Egan et al., 2011; Murakawa et al., 2019). AMPK can induce mitophagy by regulating MFN2 to respond to energy stress (Hu et al., 2021). Increased mTOR activity leads to decreased molecular activity of PINK1/Parkin and LC3 (Wen et al., 2020). In addition, AMPK inhibits mTOR signaling by phosphorylating the mTOR factors TSC2 and Raptor (Ha et al., 2015).

SIRT1 was shown to induce mitophagy and alleviate mitochondrial damage (Biel et al., 2016). Adiponectin reduces mtROS production and inhibits the generation of inflammatory cytokines TNF-α and IL-6 via mitophagy through SIRT1-PINK1 signaling (Jiang et al., 2021). The transcription factor Nrf2 is crucial in maintaining mitochondrial structure and function (Dinkova-Kostova and Abramov, 2015). The activation of Nrf2 leads to mitophagy (Dinkova-Kostova and Abramov, 2015; Gumeni et al., 2021).

BNIP3, one of the pro-apoptotic factors belonging to the Bcl-2 family, can mediate mitophagy by binding to LC3 through the LIR motif in its homodimer, which is closely related to mitochondrial function disorder and cell death (Quinsay et al., 2010; Hanna et al., 2012). Airway epithelia exposed to 7.5% CSE shows BNIP3L overproduction to promote mitophagy, resulting in enhanced mitochondrial dysfunction and cellular damage (Zhang et al., 2019). Patients with systemic inflammatory COPD show higher BNIP3- and BNIP3L-mediated mitophagy marker levels than those with normal COPD, which suggests that BNIP3-mediated mitophagy might promote systemic COPD inflammation (Leermakers et al., 2018).

The activated AMPK, ULK1, and SIRT1 signaling pathways contribute to enhance mitophagy that is highly associated with emphysema, aging, and inflammatory responses. This suggests that targeting mitophagy networks may improve the physical ability and life quality of COPD patients.

Mitochondrial biogenesis plays an important role in maintaining cellular homeostasis when stimulated by environmental factors (Popov, 2020). The mTORC1/PGC-1β signaling pathway is a master regulator of mitochondrial biogenesis in mammalian cells (Correia-Melo et al., 2016). It has been found that aging lung epithelia exhibit increased mTOR/PGC-1α/β activation, which is associated with upregulation of mitochondrial biogenesis, oxidative phosphorylation, mtROS overproduction, and induction of cellular senescence (Summer et al., 2019). The activation of mTOR induces senescence of lung cells and mimics COPD lung changes with rapid development of emphysema, pulmonary hypertension, and inflammation via phosphorylated GSK3 and Akt^ser473 signaling (Houssaini et al., 2018). In addition, the reduced lamin B1 in airway epithelia results in the decreasing expression of DEPTOR (a natural negative regulator of mTOR kinase activity) that is involved in aberrant activation of mTOR in response to CSE (Saito et al., 2019). Correspondingly, rapamycin reversed cellular senescence by reducing the activity of mTORC1/PGC-1α/β signaling, and rapamycin suppressed the expression of inflammatory cytokine SASPs (Summer et al., 2019; Walters et al., 2016). COPD patients show low mitochondrial biogenesis due to attenuated PGC-1α and TFAM (Taivassalo and Hussain, 2016). The increased PGC-1α suggests host cells enhancing mitochondrial biogenesis through up taking foreign mitochondria. This mitochondrial transfer can reverse mitochondrial malfunction in COPD (Frankenberg Garcia et al., 2022). Improving mitochondrial biogenesis to enhance mitochondrial function and muscle performance might lead to promising therapeutic strategies for COPD patients.

PGC-1α can interact with nuclear respiratory factors (Nrf1 and Nrf2) (Wu et al., 1999), members of the nuclear receptor family (such as PPARα, PPARγ, and ERR-1α), non-nuclear receptor transcription factors (such as myocyte enhancer factor-2 and MEF-2), and the FOXO family to regulate the expression of mitochondrial genes and mitochondrial transcription genes (TFAM, TFB1M, and TFB2M), leading to controlling the transcriptional activity of energy metabolism by key metabolic factors, namely, AMPK, SIRT1, and PGC-1α (Cantó and Auwerx, 2009; Gleyzer et al., 2005; Rizk et al., 2023). In addition, Parkin regulates PGC-1α at the transcriptional level, and they also interact with each other to regulate mitochondrial mass and function (Zheng et al., 2017). SIRT1 can directly interact with PGC-1α and deacetylate PGC-1α (Rodgers et al., 2005) to activate its downstream targets such as Nrf1 and TFAM to enhance mitochondrial biogenesis (Tian et al., 2019; Ye et al., 2022). In vitro SIRT1 protein levels have been reported to decrease in lung epithelia (Yao et al., 2012), endothelial cells (Arunachalam et al., 2010), and macrophages after exposure to CSE; this finding was also noticed in the lungs of smokers and patients with COPD (Rajendrasozhan et al., 2008). CS mediates pro-inflammatory responses and senescence that is associated with impaired SIRT1/FOXO3 signaling (Yao et al., 2012; Di Vincenzo et al., 2018; Yao et al., 2014). Hesperidin inhibits CSE-induced inflammatory response in a COPD rat model via modulating SIRT1/PGC-1α/NF-κB signaling (Manevski et al., 2020). In addition, SIRT1 activators inhibit TGF-β1-mediated phosphorylation of Smad3, resulting in attenuating the CSE-mediated airway remodeling of bronchial epithelia (Guan R. et al., 2020). Therefore, SIRT1 regulates PGC-1α activity at least partly via TGF-β signaling. However, the specific mechanism through which the SIRT1/PGC-1α axis regulates mitochondrial activities in COPD is yet to be known, and we need more evidence to verify the mechanism.

AMPK expression is reduced in bronchial epithelia of emphysema and CSE-exposed mice (Cui et al., 2018). Prophylactically used AMPK activators can reduce inflammation and cellular senescence in emphysema mice, which has been associated with the upregulation of mitochondrial proteins including SOD2 and SIRT3; AMPK-α1/α2 knocked down in human bronchial epithelia increases cellular senescence-related gene expression (Cheng et al., 2017). Studies have shown that mitochondrial biogenes is related with SIRT3 (Zhang et al., 2017), p-AMPK-, and TFAM (Remels et al., 2007) levels. The results indicated that they are decreasing in the skeletal muscle of COPD rats model. These findings suggest the influence of AMPK on lung inflammation and aging. However, the insight mechanism of whether AMPK signaling regulates PGC-1α in COPD needs to be verified.

Taken together, the elevated mitochondrial biogenesis is beneficial for reversing the pathogenesis of COPD. Mitochondrial homeostasis is critical for maintaining cellular survival and function; impaired mitochondrial structure and function in various cell types may induce COPD pathogenesis. However, the mechanisms by which mitochondria regulate COPD development at different stages and cell types require deep insight investments. Therefore, it might be a great challenge for the clinical application of mitochondria-targeted therapy (Figure 3).

Mitochondrial unfolded protein response, UPR^mt, is a pivotal component in maintaining immune homeostasis in response to internal or external stress (Bernales et al., 2012; Inigo and Chandra, 2022). Accumulated mtROS breaks the folding proteins and unfolded protein balance, resulting in UPR (Bernales et al., 2012). Meanwhile, mtROS overproduction can trigger UPR^mt signaling that is shown as ATF5, SIRT3, and ERα upregulation to process antioxidative activities in response to mtROS overload (Fiorese et al., 2016; Jenkins et al., 2021; Livezey et al., 2018). It is indicated that UPR^mt is associated with enhancing ELF2α and JNK phosphorylation in response to an inflammatory environment (Bernales et al., 2012; Nguyen et al., 2024; Gaspar et al., 2023). It has been suggested that UPR^mt is associated with antioxidant defense, metabolism, inflammation, etc. However, the evidence showing the mechanism of how UPR^mt contributes to COPD is limited (Kelsen, 2016). Based on our knowledge, we hypothesize that UPR^mt accumulation might prevent COPD pathogenesis in the early stage, but severe UPR^mt might play a role in COPD progression. The potential therapeutic strategies of COPD that aim at modulation of UPR^mt and mtROS need in-depth investigations.

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) serve as the bridge connecting mitochondria and ER (Zhang Y. et al., 2023; Zhang et al., 2024). MAMs play a critical role in multiple functions based on different components (Elwakiel et al., 2024), such as: 1) VDAC, and IP3R are associated with stress responses and apoptosis; 2) NLRP3 is responsible for inflammation; and 3) VDAC, IP3R, GRP75, and Mitofusin 2 (MFN2) are related with Ca²⁺ transfer to maintain homeostasis, and many others. Studies show that malfunctioning MAMs can cause extensive Ca²⁺ overloading, resulting in ER Ca²⁺ efflux into mitochondria through the VDAC1-Grp75-IP3R1 complex interacting with Cyclophilin D, which leads to disease pathogenesis (Zhang et al., 2024; Elrod et al., 2010; Baines et al., 2005). Mitochondrial dynamics-related proteins are rich in MAMs, such as MFN2, OPA1, and FIS1 (Zhang Y. et al., 2023; Elwakiel et al., 2024). Silencing or mutation of MFN2 can cause inefficient Ca²⁺ uptake, leading to health problems (Gӧbel et al., 2020; de Brito and Scorrano, 2008). Overloaded mitochondrial Ca²⁺ can further lead to mtROS, mPTP, and mtDNA release, resulting in cell death signaling (Bronner and O'Riordan, 2016; Zhong et al., 2016). Moreover, MFN2, OPA1, FIS1, etc. are involved in the mtROS homeostasis regulation (Lin H. Y. et al., 2018). It has been shown that MFN2 and OPA1 are downregulated in COPD, whereas increasing MFN2 and OPA1 expression can somehow attenuate oxidative stress and cellular senescence (Li et al., 2023; Maremanda et al., 2021). CSE can induce bronchial epithelial mtROS and senescence by enhancing mitochondrial FIS1 expression (Hara et al., 2013). Now, we can see that the overloaded Ca²⁺ will worsen the mtROS balance that might lead to UPR^mt extensive activities, which might result in unpredictable COPD development. Further understanding the relation between dysfunctional mitochondria–ER tethering proteins and mtROS overproduction, Ca²⁺ overload, and mitochondrial dynamics might provide novel therapeutic strategies of COPD.

Curcumin (CUR), a polyphenol and nontoxic compound obtained from turmeric (Curcuma longa), has been shown to exert therapeutic effects on respiratory diseases, which might be due to mitochondrial protective properties (Lelli et al., 2017). In a randomized controlled clinical study, the combination curcuminoids with piperine were shown to alleviate systemic oxidative stress and clinical symptoms in COPD patients (Panahi et al., 2016). A preclinical study indicated that CUR can improve emphysema and airway inflammation in COPD rats and reduce mitochondrial damage in alveolar epithelia (Zhang et al., 2016). CUR can also alleviate mitochondrial damage in skeletal muscle cells of COPD rats by activating PGC-1α/SIRT3 signaling (Zhang et al., 2017) and attenuate airway inflammation and airway remodeling in a COPD mouse model, which was closely related to inhibiting BEAS-2B cell proliferation and inhibiting the activation of NF-κB and cyclooxygenase-2 (COX-2) expression (Yuan et al., 2018). CUR alleviates COPD by activating SIRT1 signaling and enhancing the expression of autophagy-related proteins LC3-I, LC3-II, and Beclin-1 (Tang and Ling, 2019). These findings suggest that the mitochondrial pathway may be a potential mechanism for the treatment of COPD with CUR.

Ginsenosides (GS) from Panax ginseng (such as Rb1, Rb2, Rc, Rd, Re, Rg1, Rg3, Rg5, Rh1, and Rh2) are the main bioactive components against COPD (Chen et al., 2008; Lin et al., 2022), and ginsenosides have been found to have potential effects on mitochondrial diseases by regulating mitochondrial activities (Liu Z. et al., 2022; Zhou et al., 2019a). The anti-inflammatory effect of ginseng and ginsenosides in the treatment of COPD includes regulating the NF-κB pathway, and inflammatory cytokine (TNF-α, IL-6, IL-8, and IL-1β) expressions (Shergis et al., 2014).

Ginsenoside Rg3 treatment in the acute exacerbation COPD (AECOPD) mouse model resulted in decreased neutrophil migration and improvement of lung function and lung morphology (Guan X. et al., 2020). Ginsenoside Rg3 promoted mitochondrial biogenesis and increased PGC-1α, Nrf1, and TFAM levels (Lee et al., 2019). It can also promote mitophagy-related protein (LC3-II/LC3-I and Beclin-1) expressions by activating AMPK (Xing et al., 2017). In addition, ginsenoside Rg3 inhibits mPTP opening via scavenging free radicals to protect the mitochondrial function of nerve cells (Tian et al., 2009). Ginsenoside Rb3 might inhibit mitochondrial-associated apoptosis (Bcl-2 and BAX) and enhance energy metabolism via activating PPARα (Chen et al., 2019). It has been shown that ginsenoside Rd attenuates focal cerebral ischemia-mediated mitochondrial dysfunction that manifests by reducing mitochondrial swelling, maintaining MMP and respiratory chain complex activity, and reducing ROS production, Cyto c release, and apoptosis-inducing factor (AIF) expression (Ye et al., 2011). Additionally, ginsenoside Rd combined with Re can attenuate rotenone-induced mitochondrial damage that is associated with inhibiting MMP depolarization and increasing cytosolic and mitochondrial Ca²⁺ levels (González-Burgos et al., 2017). It is suggested that ginsenosides Rb1 and Rg1 can alleviate astrocyte impairment via reducing ROS production, increasing catalase (CAT) activity, inhibiting MMP depolarization and mtDNA content, and maintaining mitochondrial respiratory chain activity (Xu et al., 2019). Ginsenoside Rh2 promotes mitophagy via increasing PINK1/Parkin production (Hou et al., 2020). Notoginsenoside R1 (NGR1), a triterpenoid saponin compound extracted from ginseng, effectively alleviates diabetic retinopathy of db/db mice by inhibiting inflammation, reducing mtROS production, and activating PINK1-mediated mitophagy (Zhou et al., 2019b).

Increased transforming growth factor-β1 (TGF-β1) in the airway epithelium and lung cells of COPD patients promotes the recruitment of macrophages (de Boer et al., 1998; Chung et al., 2018). Ginsenoside Rg1 can not only downregulate the inflammatory response but also delay the progression of CS-induced airway remodeling by inactivating TGF-β1/Smad3 signaling (Guan et al., 2017). All these findings indicate that the properties of ginsenosides on the mitochondria are potential therapeutic strategies for COPD, and more in-depth investigations are needed to promote this natural compound to potential clinical practice.

Resveratrol (RSV) is a natural polyphenolic phytoalexin found in many fruits and vegetables with complex pharmacological effects including anti-cancer (Zhang L. X. et al., 2021). RSV shows potential benefits for COPD patients (Beijers et al., 2018). Studies have shown that RSV is associated with reducing inflammatory cell infiltration, improving the production of pro-inflammatory cytokines (TNF-α, IL-6, GM-CSF, IL-1β, and IL-8), and up-regulating antioxidant genes (SIRT1, PGC-1α, CAT, SOD1, and SOD2) in the treatment of COPD (Ma and Li, 2020; Wang et al., 2017). SIRT1 is a potential target of RSV in the treatment of COPD (Ma and Li, 2020). A mouse COPD model indicated that RSV maintains alveolar type-2 epithelial cell integrity by stimulating SIRT1 expression and promoting p53 destabilization (Navarro et al., 2017). RSV also restores steroid sensitivity of COPD lymphocytes and NKT-like cells and reduces systemic inflammatory responses by promoting SIRT1 expression (Hodge et al., 2020). RSV significantly increases PGC-1α and Nrf1 mRNA levels, mitochondrial mass, and coupled respiration through pharmacological activation of AMPK signaling to protect visual cortical neurons (Yu and Yang, 2010). RSV can upregulate antioxidant enzymes’ (SOD1, SOD2, and CAT) activities and restore reduced glutathione (GSH) biogenesis to protect astrocytes from oxidative damage (Bellaver et al., 2016).

AMPK/FOXO3 signaling is one of the vital pathways that regulate muscle atrophy; activated FOXO3 can induce the expression of atrophy-related genes, proteolysis, and muscle loss (Powers et al., 2012), and it is associated with intracellular ROS production (Akasaki et al., 2014) via NF-κB activation (Romanello et al., 2010). The ability of RSV to activate AMPK signaling to improve mitochondrial function and to increase mitochondrial biogenesis is dependent on SIRT1 (Price et al., 2012). These findings suggest that the development of new usages of RSV in COPD therapy might be via modulating mitochondrial function. However, the mechanisms of RSV anti-COPD effect via modulating mitochondrial activities need in-depth investigations.

Puerarin (PUE), an isoflavone derived from Angelica root, has various beneficial pharmacological functions (Jiang et al., 2022). The PI3K/Akt/mTOR pathway regulates autophagy, cell survival and differentiation, proliferation, and apoptosis (Hou et al., 2018), and it is involved in PM2.5-induced COPD (Mao et al., 2020). PUE can alleviate COPD by activating PI3K/Akt/mTOR signaling, inhibiting FUNDC1-mediated mitophagy and bronchial epithelial cell apoptosis (Liu J. et al., 2022).

PUE may serve as a novel and effective therapeutic agent for early-stage COPD. PUE can attenuate the acute smoking-induced infiltration of neutrophils and macrophages in mouse lung, leading to decreasing NF-κB signaling, and it also sensitively enhanced inflammatory mediator (TNF-α, COX-2, IL-6, MCP-1, and IL-8) expression; PUE also can suppress ROS production and upregulate NOX isoforms of small airway epithelia (Fang L. et al., 2022). It has been reported that PUE does not only increase mitochondrial antioxidant capacity, reduce overproduction of ROS, inhibit the expression of inflammatory factors and oxidative stress damage, and improve mitochondrial respiratory function and energy metabolism (Chang et al., 2021a) but also show mitochondrial protective properties in the treatment of nonalcoholic fatty liver disease (Wang S. et al., 2019), osteoarthritis (Wang et al., 2018), and diabetes (Chen et al., 2018).

These studies suggest that the mitochondrial pathway may be one of the mechanisms of using PUE in the treatment of COPD, but more research is needed.

Berberine (BBR) is extracted from the bark and root of Coptis chinensis (Sun et al., 2022). A preliminary study indicates that BBR exhibits anti-inflammatory effects in treating chronic airway inflammatory diseases, including COPD (Tew et al., 2020). High-dose BBR attenuates CSE-induced airway inflammation by inactivating TGF-β1/Smads signaling (Wang W. et al., 2019).

In an in vitro study, BBR-loaded liquid crystal nanoparticles can reduce the expression of oxidative stress gene Nqo1 and inflammatory mediator TNF-α in bronchial epithelia and macrophages; it also inhibits p21 expression in bronchial epithelia (Paudel et al., 2022). BBR-loaded solid lipid nanoparticles (SLNs)-chitosan nanoparticles could dramatically ameliorate inflammation scores in lung tissues and reduce inflammatory cells (neutrophils and macrophages) and inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α), thus improving the therapeutic anti-inflammatory impact of BBR against CS-induced airway inflammation in COPD rats (Sun et al., 2022).

BBR affects mitochondrial quality control and function by regulating the mitochondrial respiratory chain, oxidative stress, mitophagy, mitochondrial biogenesis and intracellular calcium concentration, and mitochondrial apoptosis (Fang X. et al., 2022). BBR can promote mitochondrial biogenesis (Yao et al., 2020) and restore autophagic flux (Hang et al., 2018) and mitochondrial energy homeostasis by regulating AMPK/PGC-1α signaling (Qin et al., 2020). BBR has also been shown to attenuate high-fat diet-induced muscle mitochondrial dysfunction by activating SIRT1/PGC-1α signaling, in which SIRT1 is involved in BBR-induced AMPK phosphorylation (Gomes et al., 2012). It is also reported that BBR protects the cardiac function of heart failure patients by upregulating PINK1/Parkin-mediated mitophagy (Abudureyimu et al., 2020) and attenuates myocardial ischemia/reperfusion impairment by regulating HIF-1α/BNIP3 signaling and enhancing mitophagy (Song et al., 2020). Furthermore, BBR inhibited NLRP3 inflammasome activation and ROS production by upregulating mitophagy, resulting in a reduction in lung inflammation in mice with influenza virus pneumonia (Liu H. et al., 2020). In addition, BBR can induce mitochondrial apoptosis, G0/G1 cell-cycle arrest, and inhibitory migration through modulating the PI3K/Akt and MAPK pathways of thyroid cancer cells (Li et al., 2017).

This suggests that BBR’s regulation of mitochondria may have an important place in new therapeutic strategies for COPD. Therefore, further studies are warranted to elucidate the detailed mechanism of the mitochondria-protective properties shown by BBR in the treatment of COPD.

Quercetin (QUE) is a plant flavanol (Zhu et al., 2018). It has been indicated that QUE protects COPD patients’ lymphocytes from 2-amino-3-methylimidazo [4, 5-f]quinoline (IQ)-induced DNA damage (Habas et al., 2018). QUE also reduces pulmonary inflammatory cell infiltration, oxidative stress, and lung function modification caused by CS exposure (da Silva Araújo et al., 2020), and it avoids emphysema changes (Araújo et al., 2022).

QUE has rhinovirus inhibitory properties in vitro and in vivo, including endocytosis, viral genome transcription, and viral protein synthesis (Ganesan et al., 2012). QUE effectively delayed lung disease progression in rhinovirus-infected COPD mice by reducing rhinovirus-induced pulmonary inflammatory cell accumulation, inhibiting mucus metaplasia and airway hyperresponsiveness (Farazuddin et al., 2018). QUE inhibits bronchial smooth muscle contraction induced by acetylcholine chloride and high K⁺ (Luo et al., 2018).

In addition, QUE modulates mitochondrial including mitochondrial quality control, mitochondria-mediated apoptosis pathways, MMP, oxidative respiratory chain and energy metabolism, and mitochondrial redox status etc. (de Oliveira et al., 2016). QUE has been shown to modulate mitochondrial properties in neuroprotective (Wang W. W. et al., 2021), cardioprotective (Chang et al., 2021b), enteroprotective (Vissenaekens et al., 2021), and hepatoprotective (Cai et al., 2021) effects. QUE reduces mtROS accumulation and subsequent NLRP3 assembly via enhancing mitophagy (Han et al., 2021). It is also known to inhibit NLRP3/caspase-1/GSDMD-N-mediated pyroptosis, maintain MMP, reduce mtDNA damage, and promote PGC-1α-mediated mitochondrial homeostasis, possibly through scavenging mtROS to protect liver cells from alcohol damage (Zhao et al., 2022). QUE was proven to upregulate SIRT1 expression, resulting in inhibiting NLRP3 activation and reducing neuroinflammation in aging mice (Li et al., 2021). It enhances the production of mitochondrial-related proteins (SIRT1, PGC-1α, and TFAM) expression (Ho et al., 2022) to inhibit apoptosis by modulating SIRT1/PGC-1α signaling (Tang et al., 2019); renal tubular epithelial cell senescence is associated with SIRT1/PINK1/Parkin activation (Liu T. et al., 2020). QUE can prevent sepsis-induced acute lung impairment and mitochondrial dysfunction by promoting the SIRT1/AMPK pathway (Sang et al., 2022). It can also restore amyloid-β-induced mitochondrial dysfunction by activating AMPK (Wang et al., 2014) and modulating the SIRT1/Nrf2/HO-1 pathway, leading to protecting the neurons in Alzheimer’s disease (Yu et al., 2020). It has been shown that QUE attenuates NF-κB signaling by inhibiting the HMGB1/TLR pathway (Li et al., 2016), and it inhibits NF-κB, TNF-α, IL-1β, IL-6, COX-2, and iNOS expression, reduces ROS levels, and increases SOD activity to attenuate Mn-induced oxidative stress and neuroinflammation (Bahar et al., 2017). Moreover, QUE was reported to downregulate mitochondrial apoptosis-related markers (BAX, Cyto c, cleaved caspase-3, and polymerase-1) and upregulate anti-apoptotic Bcl-2 expression, resulting in reduced Mn-induced apoptosis in SD rats (Bahar et al., 2017). However, on the other hand, QUE has also been reported to disrupt mitochondrial respiration between the ubiquinone pool and Cyto c that is associated with its cytotoxicity (Carrillo-Garmendia et al., 2022). It induces apoptosis and cell death of prostate cancer cells but not normal prostate epithelia via affecting mitochondrial integrity and interfering with ROS homeostasis (Ward et al., 2018).

However, few studies indicate the role of QUE-mediated mitochondrial function in the treatment of COPD. These results suggest that mitochondria may be the underlying mechanism of QUE in the treatment of COPD. However, further investigation needs to be carried out to test whether QUE has cytotoxic effects on normal cells.

Icariin (ICA) is the main biologically active monomer of natural flavonoids extracted from Epimedium brevicornum Maxim (Li et al., 2015). It was found that ICA can reduce CSE-induced pro-inflammatory cytokine secretion and oxidative damage in bronchial epithelia, and it also has a positive effect on glucocorticoid resistance (Hu et al., 2020).

ICA attenuates LPS-induced acute lung inflammation via modulating the PI3K/Akt and NF-κB pathways (Xu et al., 2010). PI3K/Akt signaling plays an important role in the regulation of the Nrf2 pathway (Martin et al., 2004). ICA is considered a potential therapeutic agent of various diseases, such as cancers, neurodegenerative diseases, osteoporosis, and cardiovascular disease due to its ability to regulate the PI3K/Akt and Nrf2 signaling pathways (Verma et al., 2022). ICA promotes mitochondrial biogenesis in human nucleus pulposus cells by activating the PI3K/Akt and Nrf2 signaling pathways and inhibits hydrogen peroxide-induced mitochondria-mediated apoptosis (Hua et al., 2020). Icariside, a derivative of ICA, protects bone marrow mesenchymal cells from damage resulting from iron overload by regulating mitochondrial morphology and fission through the MAPK and PI3K/Akt/mTOR pathways (Yao et al., 2019).

Furthermore, ICA attenuates mitochondrial oxidative damage by enhancing SIRT1 activity and maintains mitochondrial homeostasis to protect cardiomyocytes from ischemia-reperfusion caused injury (Wu et al., 2018). ICA protects neurons from rotenone damage by upregulating SIRT3 and PGC-1α expressions (Zeng et al., 2019a). This protective effect may also be related to the restoration of autophagic flux by ICA via enhancing mitophagy-related proteins’ (LC3-II and Beclin-1) expression and inhibiting mTOR activation (Zeng et al., 2019b). ICA ameliorates ROS accumulation and mitochondrial dynamics disturbance of alcohol-impaired atrium by activating SIRT3/AMPK signaling (Yu et al., 2022). ICA can rescue high glucose-induced osteoblast differentiation via inhibiting mtROS and maintaining mitochondrial homeostasis (Liu J. et al., 2022). Additionally, ICA can enhance neuronal cell activity in a triple transgenic Alzheimer’s disease mouse model via maintaining mitochondrial key enzyme COX IV and promoting ATP generation (Chen et al., 2016). The ICA and β-azalone combination increases mitophagy-related proteins’ (Beclin-1, PINK1, and p-Parkin) expression to promote autophagosomes formation, leading to attenuating amyloid-β-induced nerve cell impairment (Wang N. et al., 2021).

These studies suggest that the mitochondrial pathway may be the mechanism for icariin to treat COPD and other mitochondria-associated diseases.

Paeoniflorin (PF), a water-soluble monoterpene glucoside extracted from the root of Paeonia suffruticosa, has shown that the therapeutic effect of PF in a COPD rat model includes not only reducing airway inflammation and improving lung function but also improving oxidative stress condition by quenching ROS and upregulating antioxidant enzymes via Nrf2-dependent signaling (Lin et al., 2016).

PF can ameliorate ovalbumin-induced lung injury in a mouse model by restoring MMP, modulating mitochondrial function, and inhibiting pro-inflammatory cytokine release (Han et al., 2022). PF alleviates bortezomib-induced peripheral neuropathy (BiPN) by promoting Parkin-mediated mitophagy and decreasing IL-6 (Sun et al., 2022). In addition, PF can reduce the activities of caspase-9 and caspase-3, and it also inhibits the release of Cyto c in mitochondria, resulting in apoptosis inhibition (Liu Y. F. et al., 2022). PF can inhibit the expression of mitochondrial apoptotic proteins BAX, caspase-9, and caspase-3 and upregulate Bcl-2 by inhibiting JNK-related signaling pathways, resulting in apoptosis inhibition (Deng et al., 2022; Cong et al., 2019). PF can protect spiral ganglion neurons from cisplatin damage by reducing ROS and modulating the PINK1/BAD pathway (Yu et al., 2019). However, PF can promote apoptosis of synovial tissue by downregulating Bcl-2 and enhancing AMPK phosphorylation (Huang et al., 2021); it can promote mitochondrial biogenesis and improve TNFα-induced muscle atrophy via regulating TFAM, ERα, and Nrf1 expression (Park et al., 2022). It also improves mitochondrial dysfunction and oxidative stress induced by TNF-α by promoting the AMPK/SIRT1/PGC-1α pathway, (Li Q. et al., 2022), PF inhibits lipopolysaccharide-induced mitochondrial damage, and activation of the NLRP3 inflammasome of hepatocytes via the regulation of SIRT3/FOXO1a/SOD1 signaling (Li L. et al., 2022). Furthermore, it downregulates the ROS-NF-κB axis via suppressing NOX2/NOX4 and RAGE expression, which results in a decrease of the downstream HIF-1α/VEGF level, leading to protecting human umbilical vein endothelial cells from oxidative damage (Song et al., 2017) and inhibiting intracellular Ca²⁺ and calcium/calmodulin kinase II (CaMKII), which might show protective effects on mitochondria (Wang D. et al., 2013).

Even though few studies indicate that PF modulates mitochondrial function in COPD, the above pieces of evidence suggest that mitochondria may be the underlying molecular mechanism for PF in COPD treatment.

Paeonol (PAE) is one of the phenolic phytochemicals isolated from herbs such as Dioscorea, Paeonia lactiflora, and P. suffruticosa. PAE can reduce glutamate-induced apoptosis and neurotoxicity by suppressing Cyto c release and caspase-3 activation, as well as downregulating the ERK pathway (Wang et al., 2011). However, the mechanism of PAE in the treatment of COPD is yet to be understood. It has been shown that PAE inhibits hypoxia-mediated mitochondrial damage in pulmonary artery smooth muscle cells by decreasing ATP production, increasing ROS production, and enhancing mitochondrial morphological changes and polarization (Wang D. et al., 2019). PAE alleviates LPS-induced liver injury by improving mitochondrial function, maintaining MMP, reducing the expression of BAX and cleaved caspase-3, inhibiting superoxide production from mitochondria, and nuclear translocation of NF-κB (Xu et al., 2021).

PAE can reduce M1 macrophage polarization by inhibiting NLRP3 inflammasome, which results in decreasing inflammation levels in acute (Yuan et al., 2022). PAE can ameliorate streptozotocin-induced mtROS, TNF-α and IL-6, and MMP disturbance (Tayanloo-Beik et al., 2022). PAE derivatives have been shown to exert anti-inflammatory effects via suppressing TLR4/MyD88 signaling and inflammatory factor expression; they can also inhibit LPS-induced ROS production and restore the MMP of macrophages (Gong et al., 2022). In addition, PAE can upregulate PINK1/Parkin and BNIP3L/NIX autophagy signaling to protect retinal photoreceptor cells (Zhang D. et al., 2021). PAE can also promote apoptosis of hepatic stellate cells via inhibiting NF-κB signaling (Kong et al., 2013). PAE can induce apoptosis of cervical cancer cells that is associated with regulating the PI3K/Akt pathway to trigger mitochondrial apoptotic signaling (Du et al., 2022).

These studies suggest that PAE has potential mitochondrial protective activity, which supports the potential COPD therapy with PAE via modulating mitochondrial activities.

Hesperidin (HES), a flavonoid glycoside present in citrus fruits, has been shown to possess antioxidant, anti-inflammatory, antiviral, anticancer, and neuroprotective properties (Garg et al., 2001; Xia et al., 2018). A recent study has indicated that HES ameliorates CSE-induced inflammation and oxidative stress by promoting SIRT1/PGC-1α/NF-κB signaling (Manevski et al., 2020). Derivatives of HES, such as hesperidin-3-O-methyl ether and hesperetin-5, 7, 3-O-trimethyl ether, inhibited airway hyperresponsiveness and inflammation in mouse models (Yang et al., 2012; Shih et al., 2020).

HES can improve mitochondrial malfunction during benzopyridine-induced lung carcinogenesis in a mouse model; for example, it upregulates antioxidant and TCA cycle enzymes, protects electron transport chains, and restores ATP levels (Kamaraj et al., 2011). The mechanism by which HES treats COPD is yet to be known.

HES alleviates 6-hydroxydopamine-induced degeneration of dopamine neurons by restoring mitochondrial respiratory chain complexes-I, -IV, and V as well as Na⁺-K⁺-ATPase activity and regulating caspase-3 and caspase-9 activities (Antunes et al., 2021). HES can protect against amyloid-β-induced neurotoxicity by suppressing VDAC1-mediated mitochondrial apoptosis signaling (Wang D. M. et al., 2013). HES reduces high glucose-induced apoptosis and oxidative damage of retinal pigment epithelia via scavenging ROS, decreasing Cyto c release, and inhibiting caspase-9/3 expression (Liu et al., 2018).

Furthermore, neohesperidin attenuated hepatic steatosis and insulin resistance that was associated with increasing PGC-1α-mediated mitochondrial biogenesis in a high-fat diet mouse model (Wang et al., 2020). HES can attenuate PM2.5-induced DNA damage, cell cycle arrest, and cellular senescence of human HaCaT keratinocytes via deactivating ROS/JNK signaling (Herath et al., 2022). HES can suppress high glucose-induced DNA damage and high mitochondrial calcium level to protect neuronal cells (Lim et al., 2022). HES also inhibits apoptosis and promotes cell viability by inactivation of ERK, JNK, and MAPK (Lim et al., 2022). Additionally, HES can reverse bupivacaine anesthesia-induced decreased MMP, mitochondrial apoptotic signaling, and HES can modulate the homeostasis between redox and inflammatory system (Wang T. et al., 2021). Furthermore, HES promotes DRP1-mediated mitophagy and improves impaired mitochondria in a functional dyspepsia rat model (Jia et al., 2022).

These studies suggest that the mitochondrial pathway might provide potential insights of HES for COPD therapy.