Introduction
Mitochondria are important semiautonomous organelles, serving as the energy metabolism
center of eukaryotic cells. They can regulate cell signal transduction and maintain
cellular function and homeostasis. Mitochondrial damage involves structural damage
and mitochondrial DNA damage, playing an important role in promoting the progression
of respiratory system diseases. A large amount of clinical and experimental data suggest
that regulating mitochondrial damage may be an important target for traditional Chinese
medicine (TCM) in treating respiratory system diseases.
In TCM, it is believed that respiratory system diseases are caused by factors such
as invasion of external pathogenic factors, improper diet, emotional imbalance, and
overstrain, with complex pathogenesis and diverse patterns of syndromes. TCM treatment
focuses on harmonizing the overall function of the organs to promote the smooth flow
of qi and blood and achieve yin–yang balance. In recent years, significant progress
has been made in the TCM intervention of respiratory system diseases by regulating
mitochondrial damage. This article summarizes the role of TCM in regulating mitochondrial
damage for intervention in respiratory system diseases such as chronic obstructive
pulmonary diseases (COPDs), lung cancer, idiopathic pulmonary fibrosis (IPF), acute
lung injury (ALI), and asthma, aiming to provide a basis for the study of the pathogenesis
and drug targets of respiratory system diseases.
The Role of Mitochondrial Damage in the Occurrence and Development of Respiratory
System Diseases
Mitochondria are important semiautonomous organelles, serving as the main site for
aerobic respiration in cells and the energy metabolism center of eukaryotic cells.
They mainly synthesize adenosine triphosphate (ATP), participate in aerobic respiration,
and maintain human physiological functions. Mitochondria affects oxidative stress
and immune responses by regulating calcium signals and their homeostasis, participating
in cell differentiation, signal transduction, and apoptosis.[1] Mitochondrial damage refers to abnormal changes in mitochondrial structure and function,
including large-scale loss of mitochondrial DNA, and changes in membrane structure,
electron transfer function through the respiratory chain, mitochondrial transmembrane
potential difference, etc.,[2]
[3] resulting in mitochondrial oxidative stress, mitochondrial autophagy, mitochondrial
DNA mutations, telomere shortening, etc. A large number of studies have confirmed
that mitochondrial damage plays an important role in the occurrence and development
of respiratory system diseases.[4]
[5]
[6] Under the stimulation of factors such as hypoxia, infection, and cigarette smoke
(CS), the body produces a large amount of oxygen free radicals which promote oxidative
stress, disrupt oxidative phosphorylation, and mitochondrial homeostasis, leading
to mitochondrial dysfunction, abnormal ATP generation, and consequently causing apoptosis
of airway epithelial fibroblasts and increased mucus secretion and thus the occurrence
and development of respiratory system disease.[7] In addition, a large amount of reactive oxygen species (ROS) can damage DNA, induce
mtDNA mutations, and exacerbate cell death and mitochondrial damage.[8] Under exposure to smoke, ROS produced by mitochondria accelerates cell aging, and
lung function indicators are related to telomere shortening.[9]
Research Status of Traditional Chinese Medicine Regulation of Mitochondrial Damage
in Intervening Respiratory System Diseases
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Treating Chronic
Obstructive Pulmonary Diseases
COPD is a preventable and treatable disease characterized primarily by persistent
airflow limitation, with high morbidity and mortality rates. Epidemiological investigations
show that COPD became the third leading cause of death globally in 2020, which imposes
a heavy economic burden, with annual economic losses exceeding 100 billion U.S. dollars.[10]
[11]
[12] Mitochondrial damage caused by factors such as tobacco smoke, air pollutants, and
hypoxia is closely related to the occurrence and the development of COPD.[13]
[14] TCM has obvious advantages in treating COPD, and the mechanisms involve intervention
in inflammation, oxidative stress, mitochondrial damage, etc. The Chinese herb Hongjingtian
(Rhodiolae Crenulatae Radix et Rhizoma) is mild in nature, enters the lung and heart
meridians, and has the effects of tonifying qi and activating blood circulation, dredging
the meridians, and relieving asthma. Its extract salidroside can improve lung function,
muscle strength, body weight, and enhance ATP activity in COPD rats, alleviate mitochondrial
damage, and thus improve the prognosis of COPD.[15]
[16] Baicalin, an extract of Chinese herbs, is a flavonoid compound with anti-inflammatory,
antipyretic, and antiallergic effects. Studies have found that baicalin can significantly
inhibit mitochondrial damage and cell iron apoptosis and improve COPD induced by lipopolysaccharide
(LPS) or CS in mice.[17] The supplemented Sijunzi decoction is a famous prescription for treating “asthma,”[18] which can increase the activity of succinate dehydrogenase in skeletal muscles of
COPD model mice, alleviate mitochondrial structural damage and oxidative stress, and
enhance energy metabolism.[19] Animal experiments and clinical results have also confirmed that the compound Chinese
herbs Bufei Jianpi Granules can effectively improve the skeletal muscle function of
COPD rats, reduce the frequency of acute exacerbations in COPD patients with lung–spleen
qi deficiency by improving mitochondrial quantity and function, improve lung function,
and enhance quality of life.[20] The TCM treatment method of “cultivating earth (spleen) to generate metal (lung)”
borrows the theory of the mutual generation of the five elements, using spleen-tonifying
and qi-benefiting prescriptions to reinforce lung qi, which is used as an adjuvant
treatment for lung qi deficiency.[21] Research by Feng et al[22] has shown that the TCM compound prescription of “cultivating earth (spleen) to generate
metal (lung)” can significantly improve lung alveoli, diaphragm muscles, and mitochondrial
damage in COPD rats, relieve respiratory muscle fatigue, enhance mitochondrial function,
and reduce the occurrence of respiratory failure.
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Treating Lung Cancer
Lung cancer is a malignant tumor of the bronchial gland or mucosa, with increasing
incidence and mortality rates year by year, and is one of the most serious threats
to human health and life among malignant tumors.[23] Mitochondrial damage is closely related to the metabolic patterns of tumors, and
factors such as mitochondrial membrane damage and oxidative stress can lead to tumor
invasion and metastasis.[24]
[25] Panoxadiol is a novel antitumor drug isolated from the Chinese herb Renshen (Ginseng
Radix et Rhizoma), which is an important active ingredient of ginseng.[26] Li et al[27] used panoxadiol on lung cancer A549 cells and found that panoxadiol could reduce
the mitochondrial membrane potential of lung cancer cells, promote mitochondrial damage
of lung cancer cells, induce apoptosis of lung cancer cells, and delay the progression
of lung cancer. Fangji (Stephaniae Tetrandrae Radix) has anti-inflammatory, analgesic,
and antioxidant effects. Fangchinoline is a monomer extracted from the dried roots
of Fangji (Stephaniae Tetrandrae Radix), which can delay the development of tumors
by inducing mitochondrial apoptosis and blocking the cell cycle.[28]
[29] Chen et al[30] found that fangchinoline can effectively regulate the production of ROS caused by
mitochondrial damage, alleviate epithelial-mesenchymal transition of non-small cell
lung cancer, inhibit tumor cell invasion and migration, and exert anticancer effects.
Yinxingye (Ginkgo Folium) has the effects of astringing the lung to relieve cough
and drying dampness to stop diarrhea, mainly used for chest tightness, heart pain,
phlegm panting, and cough. Ginkgetin is a natural bis-flavonoid compound extracted
from gingko,[31] which can intervene in the cancer process by enhancing the loss of mitochondrial
membrane potential induced by cisplatin, increasing the generation of mitochondrial
ROS and apoptosis in lung cancer cells.[32]
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Idiopathic Pulmonary
Fibrosis (IPF)
IPF is a chronic, progressive, and fibrotic interstitial lung disease, which is the
main pathological manifestation of end-stage respiratory system disease. The core
pathological change of IPF is the aging and injury to alveolar epithelial cells.[33]
[34] Mitochondrial damage and autophagy defect are associated with the development of
pulmonary fibrosis, with increased mitochondrial autophagy, abnormal phenotype of
mitochondrial enlargement, increased ROS production, and cell apoptosis leading to
increased sensitivity of alveolar epithelial cells to pressure and fibrosis occurrence.[35]
[36] Rougui (Cinnamomi Cortex), also known as Guipi, is a Chinese herb with warm property
and the efficacy of warming the middle energizer to dispel cold, regulating qi and
alleviating pain. Scholars have used cinnamaldehyde to intervene in a hydrogen peroxide-induced
IPF mice model, and the experimental results showed that cinnamaldehyde can significantly
increase the level of superoxide dismutase (SOD), matrix metalloproteinase, and ATP
in IPF mice. It also restores mitochondrial structure by regulating the PINK/Parkin
signaling pathway, inhibits mesenchymal stem cell apoptosis, maintains the ability
of mesenchymal stem cells to repair alveolar epithelium, regulates cell proliferation
and migration, and participates in the pathological process of IPF.[37] Researchers have confirmed that No.2 TCM compound prescription Feibi prescription
can reduce ROS level in alveolar epithelial cells, protect mitochondrial function,
regulate antioxidant enzyme expression, alleviate mitochondrial damage, and inhibit
cell apoptosis in a ROS-induced pulmonary fibrosis model.[38] Naringin is a dihydroflavonoid compound found in naringoside, which has significant
anti-inflammatory, analgesic, and blood viscosity reducing effects.[39] Wei et al[40] investigated the impact of naringin on IPF and found that in a bleomycin-induced
mice model of IPF, naringin exhibited anti-inflammatory and antioxidant effects, inhibited
mitochondrial autophagy, maintained mitochondrial homeostasis, and alleviated cell
apoptosis, thereby intervening in the progression of IPF.
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Acute Lung Injury
Acute Lung Injury (ALI) refers to acute hypoxemic respiratory insufficiency caused
by various direct or indirect factors, with decreased lung volume, ventilation/perfusion
mismatch, and decreased lung compliance as the pathophysiological features.[41] ALI is closely related to mitochondrial damage and abnormal level of mitochondrial
mtDNA.[42] Increased production of mitochondrial oxygen free radicals, imbalance of mitochondrial
calcium homeostasis, and changes in mitochondrial permeability all affect ALI. Xuanfei
Baidu prescription is a classical Chinese medicine prescription with precise clinical
efficacy, which can clear the lung and resolve dampness, clear heat and eliminate
pathogens, purge the lung, and remove toxin.[43] Studies have reported that Xuanfei Baidu prescription can inhibit mitochondrial
dysfunction in LPS-induced ALI model mice, suppress mtDNA synthesis and replication,
reduce the expression level of inflammatory factors, and alleviate the clinical symptoms
of ALI and coronavirus disease 2019 patients.[44] Chuanxinlian (Andrographis Herba) is bitter in flavor and cold in property, with
the effects of protecting the liver and gallbladder, clearing heat and removing toxin,
as well as antibacterial and anti-inflammatory effects.[45] Its effective component, dehydroandrographolide (Deh), reduces ROS generation by
inhibiting the protein kinase B (Akt)/nuclear factor E2-related factor 2 (Nrf2) pathway,
inhibits mitochondrial damage, and may be a potential drug for treating ALI.[46] Tangeretin, a flavonoid compound, has anti-inflammatory and neuroprotective effects.[47] In studies related to the treatment of ALI induced by sepsis, tangeretin can inhibit
ROS-mediated inflammasome activation, maintain mitochondrial homeostasis in LPS-induced
ALI model mice, alleviate excessive mitochondrial fission, and thus achieve the purpose
of treating ALI.[48] Huangqin (Scutellariae Radix) is a heat-clearing and dampness-drying herb with the
effects of clearing heat and drying dampness, purging fire and detoxifying, stopping
bleeding, and calming the fetus. Baicalein, as the most abundant monomer in Huangqin
(Scutellariae Radix), has a significant clinical application value in antivirus, antibacterial,
and anti-inflammatory effects.[49] Recent studies have confirmed that baicalein can alleviate lung injury severity
and delay the progression of ALI by regulating mitochondrial damage induced by mitochondrial
division protein Drp1, downregulating the expression level of inflammatory factors
and ROS production.[50]
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Asthma
Asthma is a common chronic heterogeneous disease of the respiratory system characterized
by airway inflammation. Its clinical features primarily include airway hyperresponsiveness
and airway remodeling. The pathogenesis of asthma is complex, requiring long-term
standardized and individualized treatment.[51] Asthmatic patients accumulate airway inflammatory cells for an extended period,
leading to elevated oxidative stress level, damaging epithelial cell mitochondrial
function and homeostasis.[52]
[53] Numerous studies at home and abroad have found that apigenin has antitumor, cardiovascular
protection, and antiviral effects.[54] It can regulate the ROS-apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated
protein kinase (MAPK) pathway to reduce airway epithelial cell apoptosis, enhance
cell vitality and mitochondrial function, and inhibit inflammation and oxidative stress.[55] The extract salidroside from the root of Hongjingtian (Rhodiolae Crenulatae Radix
et Rhizoma) can enhance immune function and has anticancer and antioxidant effects.[56] Shan et al[57] found that salidroside can effectively increase mitochondrial membrane potential,
decrease ROS level and cell apoptosis levels, and improve asthma progression in bronchial
epithelial cell model induced by PM2.5. Chinese herb Mudanpi (Moutan Cortex) has the effects of clearing heat, cooling blood,
promoting blood circulation and removing blood stasis. Its main components, paeonol
and paeoniflorin, have anti-inflammatory, antipyretic, and antithrombotic effects.[58]
[59] Studies have found that paeonol and paeoniflorin can effectively improve lung injury
induced by ovalbumin (OVA) in mice and participate in asthma processes by inhibiting
the expression of inflammatory factors, restoring mitochondrial membrane potential
and mitochondrial metabolic activity and inhibiting mitochondrial autophagy.[60] The TCM prescription Bushen Yiqi prescription has the effects of tonifying qi and
kidney, promoting blood circulation and resolving masses. Research shows that Bushen
Yiqi prescription has a positive effect on the mouse model with chronic asthma. It
can reduce the generation of ROS and inhibit the expression of the inflammatory factor
nuclear factor-κB (NF-κB), lower nitric oxide (NO) expression levels in lung tissue,
improve bronchial epithelial mitochondrial structure and ATP level in the lung, alleviate
airway remodeling in the asthma model to relieve asthma symptoms.[61]
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Pneumonia
Pneumonia is mainly caused by pathogens such as bacteria and viruses, leading to infectious
inflammation of the alveoli, distal airways, and lung interstitium. It can occur at
any age, and the severity of the disease depends on the patient's immunity and the
degree of inflammation.[62]
[63] Similar to ALI, inflammation and oxidative stress are key pathological factors.
Mitochondrial damage and excessive ROS production can cause mitochondrial dysfunction,
resulting in changes in mitochondrial membrane permeability and transmembrane potential,
the release of cytochrome C from mitochondria into the cytoplasm, and leading to cell
apoptosis.[64]
[65] Glycyrrhizic acid is one of the extracts of Gancao (Glycyrrhizae Radix et Rhizoma),
with certain anticancer and antiviral effects.[66] Guan et al[67] showed that in the carbapenem-resistant Klebsiella pneumoniae (CRKP)-induced human
lung epithelial cell model by activating Nrf2 expression glycyrrhizic acid can promote
antioxidant protein production, inhibit the expression of inflammatory factors, and
alleviate mitochondrial damage and cell apoptosis, thus reducing lung tissue damage
caused by CRKP infection. Huanglian (Coptidis Rhizoma) mainly functions to clear heat,
dry dampness, purge fire, and detoxify. It is commonly used clinically to treat diarrhea,
vomiting, ulcers, swelling, and pain.[68] Berberine, also known as berberine alkaloid, isolated from Huanglian (Coptidis Rhizoma),
has broad-spectrum antibacterial effects. Liu et al[69] found that berberine can significantly inhibit the activation of NLRP3 inflammasomes
in a model of macrophage inflammation induced by influenza virus infection, increase
mitochondrial membrane potential, reduce mitochondrial oxidative stress response and
mitochondrial damage, and effectively relieve pneumonia. The TCM prescription Tongfu
Yiqi Huoxue decoction combined with alveolar lavage can exert a stable effect on pneumonia
sepsis. Its effective ingredients, astragaloside and ligustrazine, have anti-inflammatory
and antioxidant effects, which can repair mitochondrial homeostasis, inhibit peritoneal
inflammation and significantly improve clinical symptoms of pneumonia sepsis patients.[70]
Traditional Chinese Medicine Regulation of Mitochondrial Damage in Other Respiratory
System Diseases
Various functional disorders like damage of mitochondrial protein synthesis are closely
related to the progression of respiratory system diseases such as pulmonary arterial
hypertension (PAH), acute respiratory distress syndrome (ARDS), and pneumoconiosis.
Abnormal elevation of pulmonary artery pressure is a lethal pathological and physiological
state, manifesting symptoms of dyspnea, fatigue, angina pectoris, etc.,[71] which can lead to right heart failure. Studies have shown that mitochondrial dysfunction
and DNA damage are involved in the remodeling of pulmonary vasculature and right ventricle
in PAH.[72]
[73] Dilong (Pheretima), a Chinese herb used to soothe wind and relieve convulsions,
mainly functions to clear heat and arrest convulsions, dredge collaterals, relieve
asthma, and promote diuresis. Liu et al[74] found that the extract of Dilong (Pheretima) can downregulate the protein expression
of NLRP3 in lung tissue of PAH rats, reduce oxidative stress and inflammation levels
in pulmonary artery endothelial cells, alleviate apoptosis, improve mitochondrial
functional damage, and thus inhibit pulmonary vascular remodeling and PAH. Magnolol,
an important component of the Chinese herb Houpo (Magnoliae Officinalis Cortex), has
remarkable pharmacological anti-inflammatory, antibacterial, antioxidant, and anticancer
effects.[75] Chen et al[76] studied the effect of magnolol on LPS-induced ARDS and found that when magnolol
acts on pulmonary microvascular endothelial cells, the expression level of mitochondrial-dependent
Sirt3 protein is upregulated, AMP-activated protein kinase (AMPK) pathway is activated,
further inhibiting apoptosis of pulmonary microvascular endothelial cells and alleviating
ARDS. A pneumoconiosis is a group of diseases characterized by diffuse nodular or
reticular fibrosis in lung tissue caused by long-term inhalation of inorganic mineral
dust during occupational activities or in living environments.[77] Catalpol, extracted from the root and rhizome of Dihuang (Rehmanniae Radix) in the
Scrophulariaceae family, has extensive pharmacological anticancer, anti-inflammatory,
and hypoglycemic effects.[78] Through tracheal injection of quartz dust to establish a rat model of pneumoconiosis,
it was found that by regulating the peroxisome proliferator-activated receptor-γ coactivator
1α (PGC-1α)/Nrf1 and mitochondrial transcription factor A (TFAM) pathways, catalpol
can effectively protect the exercise capacity and skeletal muscle function of model
rats, enhance the ATP level of gastrocnemius muscle, restore mitochondrial membrane
potential, and inhibit oxidative stress indicator malondialdehyde level. These studies
indicate that improving mitochondrial function and alleviating oxidative stress may
be potential pathways for catalpol in the treatment of pneumoconiosis.[79]
Summary and Prospect
Various factors such as environmental pollution and aging population increasingly
affect the development of respiratory system diseases globally, seriously affecting
people's physical and mental health. The incidence and mortality of diseases of COPD,
lung cancer, asthma, and IPF have been increasing year by year. In recent years, there
have been numerous reports on the relationship between mitochondria and diseases,
involving research studies on mitochondrial autophagy, mitochondrial damage, mitochondrial
dynamics, etc., which play a positive role in studying the pathogenesis, early prevention,
and intervention of the diseases. For the past few years, the effectiveness of TCM
in regulating mitochondrial damage to intervene in diseases has been widely confirmed,
especially in the treatment of respiratory system diseases. However, the mechanism
of TCM regulation of mitochondrial damage to intervene in respiratory system diseases
is still not very clear, and it lacks relevant clinical trial data. There are still
many problems in the research, for instance: (1) the components of Chinese materia
medica are complex and diverse, making it difficult to accurately evaluate the effects
of different components on mitochondrial damage; (2) whether TCM treatment methods
such as Tuina, guiding technique, and acupuncture can affect the progression of diseases
by regulating mitochondrial damage; (3) research studies on TCM regulation of mitochondrial
damage still focus on animal cell experiments and lack clinical trial data, which
is not sufficient to guide clinical medication; and whether the therapeutic principles
of TCM syndrome differentiation and treatment can be combined with regulating mitochondrial
function to explore more individualized treatment plans for clinical application.
Therefore, further exploration is needed on the research of TCM regulation of mitochondrial
damage to intervene in respiratory system diseases.
