Oxidative Medicine and Cellular Longevity
Volume 2020 (2020), Article ID 5232614, 18 pages
https://doi.org/10.1155/2020/5232614

Research Article

Remedying the Mitochondria to Cure Human Diseases by Natural Products

Jian-Kang Mu,¹ Yan-Qin Li,¹ Ting-Ting Shi,² Li-Ping Yu,¹ Ya-Qin Yang,¹ Wen Gu,¹ Jing-Ping Li,¹ Jie Yu,¹ and Xing-Xin Yang¹

¹College of Pharmaceutical Science, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming 650500, China
²Department of Pharmaceutical Preparation, The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese medicine, Hangzhou 310023, China

Correspondence should be addressed to Jie Yu; cz.yujie@gmail.com and Xing-Xin Yang; yxx78945@163.com

Received 4 April 2020; Revised 5 June 2020; Accepted 25 June 2020; Published 14 July 2020

Academic Editor: Ratanesh K. Seth

Copyright © 2020 Jian-Kang Mu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Mitochondria are the ‘engine’ of cells. Mitochondrial dysfunction is an important mechanism in many human diseases. Many natural products could remedy the mitochondria to alleviate mitochondria-involved diseases. In this review, we summarized the current knowledge of the relationship between the mitochondria and human diseases and the regulation of natural products to the mitochondria. We proposed that the development of mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represents an attractive strategy for a mitochondria-involved disorder therapy. Moreover, investigating the mitochondrial regulation of natural products can potentiate the in-depth comprehension of the mechanism of action of natural products.

1. Introduction

As an important organelle in the cells, the mitochondria are considered the main powerhouse of the cells, because they can apply glucose, fatty acids, and certain amino acids as fuel sources to produce ATP through oxidative phosphorylation [1]. The mitochondria also play a critical role in many other processes, such as reactive oxygen species generation, maintenance of calcium homeostasis, adjustment of apoptotic cell death, regulation of lipid metabolism, and autophagy [2]. Thus, mitochondrial dysregulation of any form may lead to a variety of human diseases [2]. Mitochondrial dysfunction has been implicated in neurodegenerative disorders, cancer, liver diseases, myocardial injury, diabetes, and obesity [3, 4].

Natural products, including mixture and monomer, have been widely used to treat mitochondria-related diseases and have been reported as a highly significant source for the exploration of promising drugs/nutrients that have led to novel compounds for alleviating mitochondria-involved disorders, such as compounds with antitumor, neuroprotective, cardioprotective, hepaticprotective, antidiabetes, and antiobesity agents. The chemical synthesis of new drugs has rapidly developed in recent years with the advancement of combinatorial chemistry and computer-aided drug design technology [5]. However, due to the novel structures, therapeutic abilities, and certain unique pharmacological effects of the chemicals in natural products, the exploration of drugs and lead compounds from natural products is still an important approach for drug development [6].

The focus of this review was on mitochondrial regulation with natural products to treat human diseases. The purpose of this review was to examine the current knowledge of the relationship between mitochondria and human diseases and the regulation of natural products to the mitochondria. We proposed that the development of mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represented attractive strategies for treating mitochondria-involved disorders. Moreover, investigating mitochondrial regulation of natural products can potentiate the in-depth comprehension of the underlying mechanism of action of natural products.

2. Remedying the Mitochondria to Cure Human Diseases by Natural Products

2.1. Regulating the Mitochondria to against Cancer

Prevention of cell death is a hallmark of human cancers and a major cause of treatment failure [7]. The mitochondria control the activation of apoptotic effects or mechanisms by regulating the translocation of proapoptotic proteins from the mitochondrial intermembrane space to the cytosol [8]. In addition, the mitochondria play an important role in various forms of nonapoptotic cell death and, especially, in necroptosis [7]. Because of their role in the regulation of basic cellular functions, it is not surprising that the mitochondria are involved in many aspects of tumorigenesis and tumor progression. For example, mutations in mitochondrial DNA that affect the compositions of the mitochondrial respiratory chain will lead to ROS overproduction, inefficient ATP production, and oxidative damage to the mitochondria and other macromolecules (including DNA), thus favoring chromosomal instability and carcinogenesis [9]. Furthermore, extensive polymorphisms and mutations in the mitochondrial DNA correlated with an increased risk of developing various malignancies [10]. Therefore, inducing cancer cells to undergo mitochondrial lesions and loss of function has become a very important direction in the field of anticancer drugs.

A large number of studies have shown that natural products have a significant anticancer activity by regulating the mitochondrial function with the following main mechanisms (Table 1): (1) promote the release of proapoptotic factors and induce tumor cell apoptosis by changes in mitochondrial membrane permeability, regulation of Bcl-2 family proteins, and other pathways; (2) regulate the mitochondrial energy metabolism, including the respiratory chain and tricarboxylic acid cycle; and (3) increase ROS levels and enhances oxidative damage.

Table 1: The anticancer activity of natural products.

Types of nature products
Natural products
Mitochondrial regulation
Types of cancers
Experimental models

Mixture
Bulbine frutescens [37]
Cell cycle arrest, ROS production, apoptosis induction, disruption of ΔΨm
Triple negative and luminal breast cancer
Human breast cancer cells (MDA-MB-231 and T47D) and human embryonic kidney 293 (HEK293) cells

Bullfrog oil [38]
Increases intracellular ROS levels, maintains DNA integrity, and reduces ΔΨm
Melanoma
Human melanoma cells A2058

Monomer
Rhein [39]
Inhibits mitochondrial energy metabolism, decreases cellular ATP and ADP levels, changes the ratio of ATP to ADP, and induces mPTP opening
Liver cancer
Liver cancer cell lines (SMMC-7721 and SMMC-7721/DOX)

Orientin [40]
Increases of intracellular ROS levels in HT29 cells in a dose-dependent manner, modulates Bcl-2 family proteins, induces mitochondrial cytochrome c release into the cytoplasm in a concentration-dependent manner
Human colorectal carcinoma
Colorectal carcinoma cells (HT29)

Licochalcone A [41]
Increases the ratio of Bax/Bcl-2 and reduces the integrity of the mitochondria and promotes the release of cytochromes from mitochondria to the cytoplasm
Bladder cancer
Human bladder cancer cells (T24 and 5637)

Asparanin A [42]
Induces apoptosis through the mitochondrial pathway, including the deregulation of Bak/Bcl-xl ratio, which leads to the generation of ROS, upregulation of cytochrome c followed by decrease of ΔΨm, and activation of caspases
Endometrial cancer
Endometrial cancer cell line Ishikawa

Parameritannin A-2 [43]
The combination of doxorubicin and parameritannin A-2 remarkably increases the release of cytochrome c and the activation of caspase-3 and caspase-9
Gastric cancer
HGC27 cells

Gracillin [44]
Attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and producing ROS
Lung cancer
H1299, H460, and A549 cells

Cernumidine [45]
The combination of cernumidine and cisplatin downregulates Bcl-2 and upregulates proapoptotic Bax and depletion of the ΔΨm.
Bladder cancer
RT4, T24, and 5637 cells

2.2. Regulating the Mitochondria to against Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Friedreich’s ataxia, are strongly age related and currently cannot be cured [11]. In neurons, efficient clearance of injured mitochondria through mitophagy plays a fundamental role in mitochondrial and metabolic homeostases and neuronal survival and health [11]. The mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission [12]. Defects in fusion or fission will result in mitochondrial fragmentation, reduce energy metabolism, and increase oxidative stress, thus accelerating cell dysfunction and death, leading to neurodegenerative disease [13]. Therefore, the regulation of mitochondrial dynamics, such as fusion, fission, and mitochondrial phagocytosis, represents a significant avenue for controlling the fate of neurons [12, 13].

Through numerous animal experiments and clinical studies, a variety of drugs from natural products were identified with neuroprotective effects. Many of these drugs can exert neuroprotective effects by protecting the mitochondrial function (Table 2): (1) regulate ΔΨm and membrane fluidity; (2) protect mitochondrial structure and morphology; (3) regulate mitochondrial apoptotic pathways, reduce the release of proapoptotic factors, and inhibit neuronal apoptosis; (4) improve the cellular mitochondrial respiratory function (energy metabolism); (5) enhance superoxide dismutase (SOD) activity, inhibit oxidative stress, and reduce ROS damage; and (6) improve mitophagy.

Table 2: Neuroprotection activity of natural products.

Types of nature products
Natural products
Mitochondrial regulation
Types of diseases
Experimental models

Mixture
Solanum melongena extract [46]
Prevents apoptosis, reduces SOD, and increases ATP production and upregulates SOD and catalase activity
Rotenone-induced neurotoxicity
Rotenone-induced neurotoxicity in PC-12 cells

Ganoderma lucidum [47]
Regulates ΔΨm, radical oxygen species accumulation, and ATP depletion and activates the AMPK/mTOR and Pink1/Parkin signaling pathways
Parkinson’s disease
MPTP- (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-) induced mouse model

Monomer
Linalool [48]
Reduces mitochondrial ROS and calcium levels and maintains ΔΨm to reduce oxidative stress
Glutamate-induced nerve injury
Glutamate-induced mitochondrial oxidative stress in immortalized neuronal HT-22 cells

Cinnamic acid derivatives [49]
Blocks apoptosis and protects mitochondrial physiological functions
Neuroprotection and angiogenesis
H₂O₂-induced injury model in HBMEC-2 and SH-SY5Y cells

Proanthocyanidins [50]
Inhibits signaling pathways involved in mitochondrial-mediated apoptosis
Methyl mercuric chloride-induced neurotoxicity
Cortical neuron cells from rats

α-Arbutin [51]
Reduces oxidative stress, stabilizes ΔΨm, and enhances adenosine triphosphate
Parkinson’s disease
Rotenone-treated human neuroblastoma cells (SH-SY5Y) and drosophila Parkinson’s disease model

Naringenin [52]
Reduces oxidative load, which in turn maintains mitochondrial function and prevent neuronal cell death
H₂O₂-induced neurotoxicity
Human neuroblastoma SH-SY5Y cells

Apigenin [53]
Reduces oxidative stress, downregulates the TLR4/NF-κB signaling pathway, and inhibits mitochondrial-mediated neuronal apoptosis
Acrylonitrile-induced neuroinflammation
Acrylonitrile-induced neurotoxicity in rats

Auraptene [54]
Enhances mitochondrial respiration and attenuates ROS production
Parkinson’s disease-like behavior
Rotenone-treated SN4741 cells

Naringenin [55]
Inhibits HO-induced mitochondrial dysfunction, including a decrease in membrane potential and Bcl-2/Bax ratio, cytochrome c release, and caspase-3 cleavage
H₂O₂-induced neurotoxicity
Human neuroblastoma SH-SY5Y cells

Ulmoside A [56]
Induction of translocation of cytochrome-c, decrease of Bcl-2 level, increase of Bax level, and cleavage of caspase-3 in neuronal cells
Lipopolysaccharides- (LPS-) induced neurotoxicity
LPS-treated mouse neuroblastoma N2A cell line

Celastrol [57]
Inhibits apoptosis of dopaminergic neurons by activating mitosis and degrading damaged mitochondria
Parkinson’s disease
1-Methyl-4-phenylpyridinium- (MPP+-) induced SH-SY5Y cell model and MPTP-induced mouse model

2.3. Regulating the Mitochondria to Remedy Liver Diseases

The liver, an organ with high energy requirements, plays a pivotal role in the synthesis and secretion of multiple endogenous compounds. Liver functioning is highly dependent on the mitochondria producing ATP for biosynthetic and detoxifying properties [14]. In previous studies, it was suggested that mitochondrial dysfunction is a critical factor in the initiation and progression of liver diseases, including ischemia/reperfusion (IR) injury, nonalcoholic/alcoholic fatty liver disease (NAFLD/AFLD), nonalcoholic/alcoholic steatohepatitis (NASH/ASH), and hepatic fibrosis, as well as intoxications by xenobiotics or heavy metals, bacterial, viral, and parasitic infections [15]. The mitochondria play an important role in the process of hepatic apoptosis and necrosis. The degree of the mitochondrial activity in the liver directly affects liver function [16].

In previous studies, it was shown that some natural medicines can protect liver cells from damage or liver fibrosis by protecting the mitochondrial function (Table 3): (1) stabilize the fluidity of mitochondrial membranes and protect the structure and morphology of liver mitochondria; (2) regulate the mitochondrial apoptotic pathway, reduce the release of proapoptotic factors, and inhibit hepatocyte apoptosis; (3) increase the mitochondrial energy metabolism; and (4) enhance SOD activity, inhibit oxidative stress, and reduce ROS damage.

Table 3: Liver protection activity of natural products.

Types of nature products
Natural products
Mitochondrial regulation
Types of liver diseases
Experimental models

Mixture
Rooibos tea [58]
Enhances the ability of the respiratory chain and energy production
Liver injury
Carbon tetrachloride- (CCl₄-) induced liver damage in rats

Cimicifuga racemosa extract [59]
Maintains mitochondrial integrity and ATP levels; prevents mitochondrial ROS formation, loss of ΔΨm, and cell death; and mediates a switch from mitochondrial respiration to glycolysis
Liver injury
Erastin-treated HT22 cells and ras-selective lethal compound c-treated HepG2 cells

Sipjeondaebo-tang [60]
Improves oxidative stress and regulate ΔΨm
Liver injury
Iron/arachidonic acid-treated HepG2 and CCl₄-induced acute liver injury in mice

Polygonatum kingianum [61]
Inhibits the reduction of SOD, GSH, ATP synthase, and complex I and II, in the mitochondria; upregulates and downregulates mRNA expression of carnitine palmitoyl transferase-1 and uncoupling protein-2, respectively; inhibits the increase of caspase-9, caspase-3 and Bax expression in hepatocytes; and decreases the expression of Bcl-2 in hepatocytes and cytchrome c in the mitochondria
NAFLD
High-fat diet-induced NAFLD in rats

Punica granatum L. [62]
Decreases the expression of uncoupling protein 2 (UCP2), restores the ATP content, inhibits mitochondrial protein oxidation, and improves mitochondrial complex activity in the liver
NAFLD
High fat diet-induced NAFLD in rats and ellagic acid treated HepG2 cells

Monomer
Betaine [63]
Enhances mitochondrial function by increasing mitochondrial fusion and improves cell survival
Liver injury
Oligomycin-/rotenone-treated human HCC (Huh7) cells

Nicotinamide riboside [64]
Enhances Sirt1 and PGC-1α activity, reduces oxidative stress, and restores mitochondrial biogenesis and aerobic respiration
AFLD
Ethanol-induced AFLD in C57BL/6J mice and ethanol-treated HepG2 cells

Puerarin [65]
Improves liver complex I and complex II activity and regulates mitochondrial DNA content
NAFLD
High-fat and sucrose diet-induced NAFLD in C57BL/6J mice

Diosgenin [66]
Improves oxidative stress and increases ΔΨm
NAFLD
Palmitic acid-induced NAFLD in L-02 cells

Silybin [67]
Stimulates mitochondrial fatty acid oxidation, reduces basal and maximal respiration and ATP production in steatohepatitis cells, and rescues fatty acid-induced apoptotic signals and oxidative stress in steatohepatitis cells
NAFLD/NASH
Oleate/palmitate mixture and TNFα-treated rat hepatoma FaO cells

Salvianolic acid B [68]
Decreases cytochrome c and caspase-3 protein expression, increases mfn2 mRNA expression and ΔΨm, and enhances mitochondrial respiratory function
NASH
High-fat diet-induced NASH in rats

NecroX-7 [69]
Reduces mitochondrial ROS and intracellular ROS/RNS levels, protects ΔΨm, improves abnormal mitochondrial morphology, and reduces steatosis and oxidative damage by inhibiting mitochondrial ROS/reactive nitrogen species (RNS)
NASH
Leptin-deficient ob/ob and methionine/choline-deficient diet-fed ob/ob mice

2.4. Regulating the Mitochondria to against Diabetes and Its Complications

Diabetes mellitus (DM) is one of the most common metabolic diseases worldwide [17]. Patients with DM display hyperglycemia induced by a damage in insulin secretion (type 1), insulin action (type 2), or both. Type 1 diabetes mellitus (T1DM), which accounts for less than 10% of diabetes cases, is characterized by an immune-mediated destruction of β cells in the pancreatic islets of Langerhans, resulting in insulin deficiency [18]. Type 2 diabetes mellitus (T2DM), which accounts for less than 90% of diabetes cases, involves insulin resistance (IR) in peripheral tissues and increased levels of blood glucose, because of overnutrition with an insulin secretion defect [18, 19]. IR continuously exists in the development of T2DM. A defect in the secretion function of pancreatic beta-cell is the prerequisite of T2DM development [20]. Mitochondrial dysfunction is the common mechanism of IR and injury of secretion function of pancreatic beta-cell [20, 21]. Furthermore, many mitochondrial gene mutation sites related to diabetes have been found, and the 3243A → G mutation in the mtDNA tRNALeu(UUR) gene is the most common cause of mitochondrial diabetes [22]. This mutation results in the reduction of insulin release and insulin resistance and leads to persistent hyperglycemia, which in turn causes mitochondrial dysfunction and reduces insulin release [22]. Muscle biopsies of diabetic patients have revealed abnormal mitochondrial metabolism and reduced mitochondria quantity [23, 24].

A large proportion of the diabetic population develops chronic vascular complications leading to significant morbidity and mortality [25]. Microvascular complications include diabetic nephropathy, neuropathy, and retinopathy; muscle atrophy, coronary, and peripheral vascular diseases; and stroke [25]. The hyperglycemic milieu alters the epigenetic machinery and mtDNA. Other genes associated with mitochondrial homeostasis are epigenetically modified, thereby further contributing to mitochondrial damage [26]. Dysfunction is seen in the context of an altered mitochondrial metabolism and oxygen consumption, increased oxidative stress, and alterations to mitochondrial networking and turnover. An increasing body of evidence has highlighted the role of mitochondrial dysfunction in the development of diabetic complications [27, 28].

In previous studies, it was found that many natural products alleviated the symptoms of T2DM and its complications by protecting the mitochondrial function (Tables 4 and 5): (1) protecting the structure and morphology of the mitochondria from pathological organs/tissues; (2) regulating the mitochondrial apoptotic pathway, reducing the release of proapoptotic factors, and inhibiting cell apoptosis; (3) increasing mitochondrial energy metabolism; and (4) enhancing SOD activity, inhibiting oxidative stress, and reducing ROS damage.

Table 4: Anti-T2DM activity of natural products.

Types of nature products
Natural products
Mitochondrial regulation
Experimental models

Mixture
Polysaccharides from Portulaca oleracea L. [70]
Improves ΔΨm, increases ATP production, depolarizes cell membrane potential, and increases intracellular Ca²⁺ levels
Tetrodotoxin-treated INS-1 cells

Korean red ginseng [71]
Increases mtDNA copy number of mitochondrial biogenesis-related transcription factors (PGC-1α and T-fam)
C57BL/KsJ db/db mice (a genetic animal model of obese T2DM)

Monomer
Berberine [72]
Reduces mitochondrial ROS levels primarily through Sirt3 modification
Arsenic-induced Sirt3 modifications in isolated mitochondria from rat pancreas

Quercetin [73]
Reduces ROS, increases complex I activity and electron transfer system coupling efficiency, increases cellular NAD/NADH ratio, and activates the PGC-1α mediated pathway
High-glucose-stimulated HepG2 cells

Theaflavins [74]
Enhances the mitochondrial DNA copy number, downregulates the PGC-1 β mRNA level, and increases PRC mRNA expression
Palmitic acid-induced I/R in HepG2 cells

Silibinin [75]
Improves mitochondrial quality, regulates ΔΨm, and increases the Bcl-2/Bax ratio
Palmitic acid-induced apoptosis and mitochondrial dysfunction in pancreatic INS-1 cells

Puerarin [76]
Improves the tricarboxylic acid cycle and oxidative phosphorylation function of the mitochondria of skeletal muscle, enhances the expression levels of regulators of mitochondrial biogenesis (Sirt 1 and PGC-1α), and increases the density of the mitochondria
High-fat diet-/streptozocin-induced diabetic rats and palmitate acid-treated rat L6 skeletal muscle cells

Table 5: Antidiabetic complications activity of natural products.

Types of nature product
Natural products
Mitochondrial regulation
Cured complications
Experimental models

Mixture
QiDiTangShen granules [77]
Improves mitochondrial quality and increases the expression of Sirt1 and the proportion of p-AMPK (thr172)/AMPK
Nephropathy
db/db mice

Shengmai San [78]
Increases protein levels of complexes I, III, and V and regulates the activity of oxidative phosphorylation complexes I and IV
Cardiomyopathy
Leptin receptor-deficient db/db mouse and palmitate acid-treated H9C2 cells

Water extracts of Liuwei Dihuang [79]
Improves ΔΨm and inhibits NADPH oxidase activation, and ROS production
Muscle atrophy
Methylglyox-treated C2C12 myotubes and streptozocin-treated C57BL/6 mice

Monomer
Anthocyanins [80]
Inhibits the generation of ROS, cellular apoptosis, expression of cleaved caspase-3 and the Bax/Bcl-2 ratio and enhances the expression of cytochrome c released from mitochondria
Nephropathy
BKS db/db c57BL6 mice and high-glucose-stimulated HK-2 cells

Orientin [81]
Regulates ΔΨm and the activation of mitophagy
Nephropathy
High-glucose-treated MPC-5 cells

Salidroside [82]
Increases mitochondrial DNA copy and electron transport chain proteins and improves the reduction of Sirt1 and PGC-1α expression
Nephropathy
Streptozotocin-induced diabetic nephropathy in obese mice

Astragalus polysaccharides [83]
Inhibits the expression of proapoptotic proteins of both the extrinsic and intrinsic pathways and modulates the ratio of Bcl-2 to Bax in the mitochondria
Cardiomyopathy
High-glucose-stimulated H9C2 cells

Ginsenoside Rb1 [84]
Reduces mitochondrial damage and activates oxygen production, enhances the Bcl-2/Bax ratio, and inhibits the expression of cleaved caspase-3 and cleaved caspase-9
Encephalopathy
Methylglyoxal-induced damage in SH-SY5Y cells

Hydroxytyrosol [85]
Increases mitochondrial complex IV and HO-1 expression through activating the AMPK pathway, followed by preventing the high-glucose-induced production of ROS and reduces cell viability
Neuropathy
Male db/db C57BL/6J mice and SH-SY-5Y neuroblastoma cells

2.5. Regulating the Mitochondria to Antiobesity

Obesity is caused by an imbalance between energy intake and expenditure and results in excessive energy that in adipose tissue is stored as triglycerides (TGs) [29]. It is not only recognized as a simple condition but also causes many metabolic diseases, such as cardiovascular disease, T2DM, hypertension, and fatty liver disease [30]. In many organs and tissues (including adipose tissue), the mitochondria are center stage in the control of energy homeostasis. Research evidence indicates that mitochondrial dysfunction in adipocytes is closely related to obesity [31]. Various physiological conditions, such as excessive nutrition and genetic factors, disrupt mitochondrial function by impairing mitochondrial biogenesis, dynamics, and oxidative capacity. Mitochondrial dysfunction in adipocytes may have impact on adipogenesis and insulin sensitivity and may significantly alter their metabolic function, which ultimately leads to obesity [32].

Animal experiments and clinical studies have successively identified many drugs from natural products for treating obesity. Many of these drugs can regulate mitochondrial function to treat obesity, primarily through promoting energy and fat metabolism (Table 6).

Table 6: Antiobesity activity of natural products.

Types of nature products
Natural products
Mitochondrial regulation
Experimental models

Mixture
Green tea [86]
Moderates CPT-1 and ACAA2 levels and reduces CPT-2 and ACAD levels
High-fat diet-induced obese in C57BL/6 mice

Peanut sprout extracts [87]
Promotes mitochondrial fatty acid oxidation
Dibutyryl cyclic adenosine monophosphate- (cAMP-) stimulated 3T3-L1 cells and rosiglitazone-stimulated C3H10T1/2 cells

Melinjo (Gnetum gnemon L.) seed extract [88]
Upregulates thermogenic uncoupling protein 1 (UCP1) and mitochondrial marker cytochrome c oxidase subunit IV protein expression in brown adipose tissue
High-fat diet-fed C57BL6J mice

Cinnamomum cassia Presl [89]
Increases ATP levels by increasing the mRNA expression of mitochondrial biogenesis-related factors, such as PGC-1α, Nrf1, and T-fam
High-fat diet-induced obese mouse and mouse C2C12 myoblasts

Guarana (Paullinia cupana Kunth) [90]
Increases the expression of PGC-1α, CREB1, AMPKA1, Nrf1, Nrf2, and Sirt1 in the muscle and brown adipose tissue and increases mtDNA (mitochondrial DNA) content in the muscle
High-fat diet-fed C57BL6J mice

Monomer
Isorhamnetin [91]
Regulates mitochondrial biosynthetic mRNA levels of PGC-1α, Nrf1, and T-fam and increases the mtDNA/nuclear DNA ratio
3T3-L1cells

Zeaxanthin [92]
Increases mitochondrial DNA content and mRNA levels of genes related to mitochondrial biogenesis, reduces mitochondrial oxidative damage, improves ΔΨm, and eliminates intracellular ROS and mitochondrial superoxide
3T3-L1 preadipocytes

Berberine [93]
In a mouse model, protects mitochondrial structure and function by reducing ATP abundance and activity of complex I and enhances the activity of complexes II and IV. In a cellular model, decreases ATP abundance, increases ΔΨm and inhibits apoptosis
High-fat diet-induced obese model in C57BL/6 mice with GLP-1 reduction

Purpurin [94]
Regulates ROS and reduces ΔΨm and ATP production
3T3-L1 murine preadipocytes and high-fat diet-fed C57BL/6 mice

Epigallocatechin-3-gallate [95]
Increases the mtDNA content and the mRNA levels of PGC-1α, Nrf1, and T-fam in brown adipose tissue
High-fat diet-induced obesity in C57BL/6J mice

2.6. Regulating the Mitochondria to against Myocardial Injury

Myocardial injury can be caused by myocardial infarction, ischemia, inflammatory cell infiltration, poisoning, and so on [33]. The essence of myocardial injury refers to the edema, degeneration, and necrosis of myocardial cells; the breakdown and lysis of myofibrils; and cellular structures, such as mitochondria in severe lesions. Severe myocardial injury can lead to myocarditis and heart failure [34]. Myocardium is the most energy consuming tissue in the human body [35]. Mitochondrial abnormalities play a central role in the pathogenesis and development of various heart diseases, including acute myocardial infarction and cardiomyopathy [36].

In previous studies, it was shown that natural products can protect the heart by regulating the mitochondrial function (Table 7): (1) stabilize ΔΨm and membrane fluidity; (2) protect mitochondrial structure and morphology; (3) adjust mitochondrial apoptotic pathways, reduce the release of proapoptotic factors, and inhibit myocardial cell apoptosis; (4) improve mitochondrial energy metabolism; and (5) enhance SOD and GSH activity, inhibit oxidative stress, and reduce ROS damage.

Table 7: Antimyocardial injury of natural products.

Types of natural products
Natural products
Mitochondrial regulation
Types of diseases
Experimental models

Mixture
Propolis [96]
Reduces the rate of H₂O₂ produced by mitochondrial respiration
Myocardial ischemia
Hypothermia-induced ischemia model in C57BL6J mice

Monomer
Capsaicin [97]
Inhibits the production of ROS, inhibits opening of the mPTP and activation of caspase-3, downregulates Bax, and upregulates Bcl-2
I/R injury
Acute myocardial hypoxia/reoxygenation (H/R) injury model in H9C2 cells

Quercetin [98]
Increases cell viability, SOD, catalase, and GPx activity, GSH levels, ΔΨm, and GSH/GSSG ratios and reduces LDH and caspase-3 activity, MDA and ROS levels, mPTP openness and the percentage of apoptotic cells
Doxorubicin-caused cardiotoxicity
Doxorubicin-treated cardiomyocytes

Luteoloside [99]
Decreases levels of lactate dehydrogenase, ROS species, mPTP openness, caspase-3 activity, and apoptotic rate
I/R injury
H/R-induced I/R model in H9C2 cardiomyocytes

Astragaloside IV [100]
Upregulates mitochondrial Bcl-2 expression, enhances antioxidant capacity, inhibits ROS, increases oxygen consumption, maintains ΔΨm, and inhibits mPTP opening and apoptosis
I/R injury
H/R-treated H9C2 cells and anoxia/reoxygenation model in isolated rat heart

Eriodictyol [101]
Suppresses the overload of intracellular Ca²⁺, prevents the overproduction of ROS, blocks mPTP opening, increases the ΔΨm level, and decreases ATP depletion and upregulates Bcl-2 expression and downregulates Bax and caspase-3 expression
Myocardial infarction
H/R-induced I/R model in H9C2 cardiomyocytes

Dihydromyricetin [102]
Increases ATP content, mitochondrial DNA content, and citrate synthase activity and decreases ROS level, mitochondrial MnSOD activity, and caspase-3 activity
I/R injury
I/R model in mice and H/R-treated cardiomyocytes from mice

Vitexin [103]
Reduces ROS levels; improves mitochondrial activity, ΔΨm, and ATP content; increases mfn2 expression, and reduces the recruitment of Drp1 in the mitochondria
I/R injury
I/R model in isolated rat heart and H/R-induced I/R model in H9C2

Honokiol [104]
Inhibits ROS production and regulates ΔΨm.
I/R injury
I/R model in C57BL/6 mice and H/R-treated cardiomyocytes from neonatal rats

Apigenin [105]
Reduces the activity of lactate dehydrogenase and intracellular ROS, alleviates the loss of ΔΨm, prevents mPTP opening, and decreases caspase-3 activity, cytochrome c release, and apoptosis
I/R injury
I/R model in isolated rat heart and ischemic/reperfusion medium-induced injury model in cardiomyocytes

3. Similarities and Differences between the Mitochondrial Mechanisms for Natural Products Regulating Different Diseases

As shown in Table 8, there are some common mechanisms in mitochondrial dysfunction among different diseases, and the similarities and differences existed between the mitochondrial mechanisms for natural products regulating different diseases. For instance, almost all the mitochondria-involved diseases, including neurodegenerative disorders, cancer, liver diseases, myocardial injury, diabetes, and obesity, are related with mitochondrial energy metabolism, which can be remedied by natural products. However, fatty acid oxidation is specifically involved with obesity and fatty liver disease, which can also be regulated by natural products. Furthermore, a variety of natural products can remedy the mitochondria through multiple mechanisms to cure various diseases.

Table 8: Similarities and differences between the mitochondrial mechanisms for natural products regulating different diseases.

Diseases
Major mechanisms
Natural products

Cancer
Energy metabolism obstruction
Rhein [39]

Gracillin [44]

Oxidative stress
Bulbine frutescens [37]

Bullfrog oil [38]

Orientin [40]

Asparanin A [42]

Gracillin [44]

Apoptosis
Bulbine frutescens [37]

Orientin [40]

Licochalcone A [41]

Asparanin A [42]

Parameritannin A-2 [43]

Cernumidine [45]

Mitochondrial membrane potential imbalance
Bullfrog oil [38]

Rhein [39]

Asparanin A [42]

Cernumidine [45]

Neurodegenerative diseases
Energy metabolism obstruction
Solanum melongena extract [46]

Ganoderma lucidum [47]

α-Arbutin [51]

Auraptene [54]

Oxidative stress
Solanum melongena extract [46]

Linalool [48]

α-Arbutin [51]

Naringenin [52]

Apigenin [53]

Auraptene [54]

Apoptosis
Ganoderma lucidum [47]

Cinnamic acid derivatives [49]

Proanthocyanidins [50]

Naringenin [52]

Apigenin [53]

Naringenin [55]

Ulmoside A [56]

Mitochondrial membrane potential imbalance
Ganoderma lucidum [47]

Linalool [48]

α-Arbutin [51]

Mitochondrial fusion, division, and autophagy
Celastrol [57]

Liver diseases
Energy metabolism obstruction
Rooibos tea [58]

Cimicifuga racemosa extract [59]

Polygonatum kingianum [61]

Betaine [63]

Nicotinamide riboside [64]

Puerarin [65]

Punica granatum L. [62]

Silybin [67]

Salvianolic acid B [68]

Oxidative stress
Cimicifuga racemosa extract [59]

Sipjeondaebo-tang [60]

Polygonatum kingianum [61]

Nicotinamide riboside [64]

Diosgenin [66]

Silybin [67]

NecroX-7 [69]

Apoptosis
Cimicifuga racemosa extract [59]

Polygonatum kingianum [61]

Betaine [63]

Silybin [67]

Salvianolic acid B [68]

Mitochondrial membrane potential imbalance
Cimicifuga racemosa extract [59]

Sipjeondaebo-tang [60]

Diosgenin [66]

Salvianolic acid B [68]

NecroX-7 [69]

Fatty acid oxidation
Silybin [67]

NecroX-7 [69]

T2DM
Energy metabolism obstruction
Polysaccharides from Portulaca oleracea L. [70]

Korean red ginseng [71]

Berberine [72]

Quercetin [73]

Theaflavins [74]

Puerarin [76]

Mitochondrial membrane potential imbalance
Polysaccharides from Portulaca oleracea L. [70]

Silibinin [75]

Apoptosis
Silibinin [75]

Mitochondrial fusion, division, and autophagy
Korean red ginseng [71]

Quercetin [73]

Theaflavins [74]

Silibinin [75]

Puerarin [76]

Diabetes complications
Energy metabolism obstruction
QiDiTangShen granules [77]

Shengmai San [78]

Water extracts of Liuwei Dihuang [79]

Salidroside [82]

Hydroxytyrosol [85]

Oxidative stress
Water extracts of Liuwei Dihuang [79]

Anthocyanins [80]

Ginsenoside Rb1 [84]

Hydroxytyrosol [85]

Apoptosis
Anthocyanins [80]

Orientin [81]

Astragalus polysaccharides [83]

Ginsenoside Rb1 [84]

Mitochondrial membrane potential imbalance
Orientin [81]

Water extracts of Liuwei Dihuang [79]

Mitochondrial fusion, division, and autophagy
Orientin [81]

QiDiTangShen granules [77]

Salidroside [82]

Obesity
Energy metabolism obstruction
Melinjo (Gnetum gnemon L.) seed extract [88]

Cinnamomum cassia Presl [89]

Isorhamnetin [91]

Zeaxanthin [92]

Berberine [93]

Purpurin [94]

Epigallocatechin-3-gallate [95]

Guarana (Paullinia cupana Kunth) [90]

Mitochondrial membrane potential imbalance
Zeaxanthin [92]

Berberine [93]

Purpurin [94]

Mitochondrial fusion, division, and autophagy
Cinnamomum cassia Presl [89]

Isorhamnetin [91]

Zeaxanthin [92]

Epigallocatechin-3-gallate [95]

Guarana (Paullinia cupana Kunth) [90]

Fatty acid metabolism
Green tea [86]

Myocardial injury
Energy metabolism obstruction
Propolis [96]

Luteoloside [99]

Eriodictyol [101]

Dihydromyricetin [102]

Vitexin [103]

Apigenin [105]

Oxidative stress
Capsaicin [97]

Quercetin [98]

Luteoloside [99]

Astragaloside IV [100]

Eriodictyol [101]

Dihydromyricetin [102]

Vitexin [103]

Honokiol [104]

Apigenin [105]

Apoptosis
Capsaicin [97]

Quercetin [98]

Luteoloside [99]

Astragaloside IV [100]

Eriodictyol [101]

Dihydromyricetin [102]

Apigenin [105]

Mitochondrial membrane potential imbalance
Capsaicin [97]

Quercetin [98]

Luteoloside [99]

Astragaloside IV [100]

Eriodictyol [101]

Vitexin [103]

Honokiol [104]

Apigenin [105]

4. Conclusion

Mitochondria are cytoplasmic organelles responsible for cell survival and cell death. Mitochondrial dysfunction has been reported to be involved in many diseases. Many natural products can regulate the mitochondria in various ways to alleviate related diseases (Figure 1). However, only a few have become clinical drugs for treating patients, and many compounds have not been used in clinical practice. Additional studies (such as pharmacodynamics, toxicology, and structure-activity relationship) of these compounds should be performed, which will promote that more natural products will be available for clinical usage. In addition, the monomers that can regulate the mitochondria in many natural extracts remain unclear, and further studies are warranted to identify natural monomers that can regulate the mitochondria. With the deepening of research, it is believed that more natural products that can regulate the mitochondria have the potential to be used in treating diseases, which is of utmost importance.

Figure 1: Remedying the mitochondria to cure human diseases by natural products.

Abbreviations

AFLD: | Alcoholic fatty liver disease
ASH: | Alcoholic steatohepatitis
DM: | Diabetes mellitus
H/R: | Hypoxia/reoxygenation
I/R: | Ischemia/reperfusion
IR: | Insulin resistance
LPS: | Lipopolysaccharides
ΔΨm: | Mitochondrial membrane potential
MPTP: | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NAFLD: | Nonalcoholic fatty liver disease
NASH: | Nonalcoholic steatohepatitis
T1DM: | Type 1 diabetes mellitus
T2DM: | Type 2 diabetes mellitus.

Data Availability

My article is a summary, so there is no data to provide.

Consent

Publication of this manuscript has been approved by all co-authors.

Conflicts of Interest

The authors declare that there is no duality of interest associated with this manuscript.

Authors’ Contributions

Jian-Kang Mu and Yan-Qin Li have contributed equally to this work.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (Grants 81660596, 81460623, and 81760733) and the Application and Basis Research Project of Yunnan China (Grants 2019FF002-061 and 2017FF117-013).

References

F. Wang, M.-A. Ogasawara, and P. Huang, “Small mitochondria-targeting molecules as anti-cancer agents,” Molecular Aspects of Medicine, vol. 31, no. 1, pp. 75–92, 2010.

J. R. Friedman and J. Nunnari, “Mitochondrial form and function,” Nature, vol. 505, no. 7483, pp. 335–343, 2014.

V. Eisner, M. Picard, and G. Hajnóczky, “Mitochondrial dynamics in adaptive and maladaptive cellular stress responses,” Nature Cell Biology, vol. 20, no. 7, pp. 755–765, 2018.

J. B. Spinelli and M. C. Haigis, “The multifaceted contributions of mitochondria to cellular metabolism,” Nature Cell Biology, vol. 20, no. 7, pp. 745–754, 2018.

Y. Wang, X. Fan, H. Qu, X. Gao, and Y. Cheng, “Strategies and techniques for multi-component drug design from medicinal herbs and traditional chinese medicine,” Current Topics in Medicinal Chemistry, vol. 12, no. 12, pp. 1356–1362, 2012.

B. Wang, J. Deng, Y. Gao, L. Zhu, R. He, and Y. Xu, “The screening toolbox of bioactive substances from natural products: A review,” Fitoterapia, vol. 82, no. 8, pp. 1141–1151, 2011.

S. Fulda, “Tumor resistance to apoptosis,” International Journal of Cancer, vol. 124, no. 3, pp. 511–515, 2009.

P. Golstein and G. Kroemer, “Cell death by necrosis: towards a molecular definition,” Trends in Biochemical Sciences, vol. 32, no. 1, pp. 37–43, 2007.

A.-V. Kudryavtseva, G.-S. Krasnov, A.-A. Dmitriev et al., “Mitochondrial dysfunction and oxidative stress in aging and cancer,” Oncotarget, vol. 7, no. 29, pp. 44879–44905, 2016.

J.-A. Petros, A.-K. Baumann, E. Ruiz-Pesini et al., “mtDNA mutations increase tumorigenicity in prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 3, pp. 719–724, 2005.

G. Lou, K. Palikaras, S. Lautrup, M. Scheibye-Knudsen, N. Tavernarakis, and E. F. Fang, “Mitophagy and neuroprotection,” Trends in Molecular Medicine, vol. 26, no. 1, pp. 8–20, 2020.

K. Panchal and A.-K. Tiwari, “Mitochondrial dynamics, a key executioner in neurodegenerative diseases,” Mitochondrion, vol. 47, pp. 151–173, 2019.

Y. Luo, A. Hoffer, B. Hoffer, and X. Qi, “Mitochondria: a therapeutic target for Parkinson’s disease?” International Journal of Molecular Sciences, vol. 16, no. 9, pp. 20704–20730, 2015.

X. Zhang, X. Wu, Q. Hu et al., “Mitochondrial DNA in liver inflammation and oxidative stress,” Life Sciences, vol. 236, article 116464, 2019.

E. Crosas-Molist and I. Fabregat, “Role of NADPH oxidases in the redox biology of liver fibrosis,” Redox Biology, vol. 6, pp. 106–111, 2015.

T.-A. Ajith, “Role of mitochondria and mitochondria-targeted agents in non-alcoholic fatty liver disease,” Clinical and Experimental Pharmacology and Physiology, vol. 45, no. 5, pp. 413–421, 2018.

A.-M. Schmidt, “Diabetes mellitus and cardiovascular disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 39, no. 4, pp. 558–568, 2019.

S. Fujimaki and T. Kuwabara, “Diabetes-induced dysfunction of mitochondria and stem cells in skeletal muscle and the nervous system,” International Journal of Molecular Sciences, vol. 18, no. 10, p. 2147, 2017.

D. M. D'Souza, D. Al-Sajee, and T. J. Hawke, “Diabetic myopathy: impact of diabetes mellitus on skeletal muscle progenitor cells,” Frontiers in Physiology, vol. 4, p. 379, 2013.

F. Zatterale, M. Longo, J. Naderi et al., “Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes,” Frontiers in Physiology, vol. 10, p. 1607, 2020.

Y. Lin and Z. Sun, “Current views on type 2 diabetes,” The Journal of Endocrinology, vol. 204, no. 1, pp. 1–11, 2010.

L. Vilarinho, F.-M. Santorelli, I. Coelho et al., “The mitochondrial DNA A3243G mutation in Portugal: clinical and molecular studies in 5 families,” Journal of the Neurological Sciences, vol. 163, no. 2, pp. 168–174, 1999.

E. Heyman, F. Daussin, V. Wieczorek et al., “Muscle oxygen supply and use in type 1 diabetes, from ambient air to the mitochondrial respiratory chain: is there a limiting step?” Diabetes Care, vol. 43, no. 1, pp. 209–218, 2020.

T. Jelenik, U. Flögel, E. Álvarez-Hernández et al., “Insulin resistance and vulnerability to cardiac ischemia,” Diabetes, vol. 67, no. 12, pp. 2695–2702, 2018.

N.-B. Flemming, L.-A. Gallo, M.-S. Ward, and J.-M. Forbes, “Tapping into mitochondria to find novel targets for diabetes complications,” Current Drug Targets, vol. 17, no. 12, pp. 1341–1349, 2016.

R.-A. Kowluru, “Mitochondrial stability in diabetic retinopathy: lessons learned from epigenetics,” Diabetes, vol. 68, no. 2, pp. 241–247, 2019.

R. Blake and I.-A. Trounce, “Mitochondrial dysfunction and complications associated with diabetes,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1840, no. 4, pp. 1404–1412, 2014.

P.-Z. Wei and C.-C. Szeto, “Mitochondrial dysfunction in diabetic kidney disease,” Clinica Chimica Acta, vol. 496, pp. 108–116, 2019.

E. Björnson, M. Adiels, M.-R. Taskinen, and J. Borén, “Kinetics of plasma triglycerides in abdominal obesity,” Current Opinion in Lipidology, vol. 28, no. 1, pp. 1–18, 2016.

M. Blüher, “Adipose tissue dysfunction contributes to obesity related metabolic diseases,” Best Practice & Research. Clinical Endocrinology & Metabolism, vol. 27, no. 2, pp. 163–177, 2013.

A.-H. de Mello, A.-B. Costa, J.-D.-G. Engel, and G.-T. Rezin, “Mitochondrial dysfunction in obesity,” Life Sciences, vol. 192, pp. 26–32, 2018.

C.-S. Lai, J.-C. Wu, C.-T. Ho, and M.-H. Pan, “Chemoprevention of obesity by dietary natural compounds targeting mitochondrial regulation,” Molecular Nutrition & Food Research, vol. 61, no. 6, 2017.

S. Hernandez-Resendiz, K. Chinda, S.-B. Ong, H. Cabrera-Fuentes, C. Zazueta, and D. J. Hausenloy, “The role of redox dysregulation in the inflammatory response to acute myocardial ischaemia-reperfusion injury - adding fuel to the fire,” Current Medicinal Chemistry, vol. 25, no. 11, pp. 1275–1293, 2018.

M. Neri, I. Riezzo, N. Pascale, C. Pomara, and E. Turillazzi, “Ischemia/reperfusion injury following acute myocardial infarction: a critical issue for clinicians and forensic pathologists,” Mediators of Inflammation, vol. 2017, Article ID 7018393, 14 pages, 2017.

J.-L. Pohjoismäki and S. Goffart, “The role of mitochondria in cardiac development and protection,” Free Radical Biology & Medicine, vol. 106, pp. 345–354, 2017.

M. Jašová, I. Kancirová, I. Waczulíková, and M. Ferko, “Mitochondria as a target of cardioprotection in models of preconditioning,” Journal of Bioenergetics and Biomembranes, vol. 49, no. 5, pp. 357–368, 2017.

P. P. Kushwaha, P. S. Vardhan, P. Kapewangolo et al., “Bulbine frutescens phytochemical inhibits notch signaling pathway and induces apoptosis in triple negative and luminal breast cancer cells,” Life Sciences, vol. 234, article 116783, 2019.

L. Amaral-Machado, W. N. Oliveira, É. N. Alencar et al., “Bullfrog oil (Rana catesbeiana Shaw) induces apoptosis, in A2058 human melanoma cells by mitochondrial dysfunction triggered by oxidative stress,” Biomedicine & Pharmacotherapy, vol. 117, article 109103, 2019.

L. Wu, K. Cao, Z. Ni et al., “Rhein reverses doxorubicin resistance in SMMC-7721 liver cancer cells by inhibiting energy metabolism and inducing mitochondrial permeability transition pore opening,” BioFactors, vol. 45, no. 1, pp. 85–96, 2019.

K. Thangaraj, B. Balasubramanian, S. Park, K. Natesan, W. Liu, and V. Manju, “Orientin induces G0/G1 cell cycle arrest and mitochondria mediated intrinsic apoptosis in human colorectal carcinoma HT29 cells,” Biomolecules, vol. 9, no. 9, p. 418, 2019.

S. H. Hong, H.-J. Cha, H. Hwang-Bo et al., “Anti-proliferative and pro-apoptotic effects of licochalcone a through ROS-mediated cell cycle arrest and apoptosis in human bladder cancer cells,” International Journal of Molecular Sciences, vol. 20, no. 15, p. 3820, 2019.

F. Zhang, Y.-Y. Zhang, Y.-S. Sun et al., “Asparanin a from asparagus officinalis L. induces G0/G1 cell cycle arrest and apoptosis in human endometrial carcinoma ishikawa cells via mitochondrial and PI3K/AKT signaling pathways,” Journal of Agricultural and Food Chemistry, vol. 68, no. 1, pp. 213–224, 2019.

L. Liang, A. Amin, W.-Y. Cheung et al., “Parameritannin A-2 from Urceola huaitingii enhances doxorubicin-induced mitochondria-dependent apoptosis by inhibiting the PI3K/Akt, ERK1/2 and p38 pathways in gastric cancer cells,” Chemico-Biological Interactions, vol. 316, article 108924, 2020.

H.-Y. Min, H.-J. Jang, K. H. Park et al., “The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II,” Cell Death & Disease, vol. 10, no. 11, p. 810, 2019.

M. A. Miranda, A. Mondal, M. Sachdeva et al., “Chemosensitizing effect of cernumidine extracted from solanum cernuum on bladder cancer cells in vitro,” Chemistry & Biodiversity, vol. 16, no. 10, article e1900334, 2019.

Y. Youn, S.‐. H. Jeon, H.‐. Y. Jin, D. N. Che, S.‐. I. Jang, and Y.‐. S. Kim, “Chlorogenic acid-rich Solanum melongena extract has protective potential against rotenone-induced neurotoxicity in PC-12 cells,” Journal of Food Biochemistry, vol. 43, no. 11, article e12999, 2019.

Z.-l. Ren, C.-d. Wang, T. Wang et al., “Ganoderma lucidum extract ameliorates MPTP-induced parkinsonism and protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis,” Acta Pharmacologica Sinica, vol. 40, no. 4, pp. 441–450, 2019.

A. M. Sabogal-Guáqueta, F. Hobbie, A. Keerthi et al., “Linalool attenuates oxidative stress and mitochondrial dysfunction mediated by glutamate and NMDA toxicity,” Biomedicine & Pharmacotherapy, vol. 118, article 109295, 2019.

W.-X. Zhang, H. Wang, H.-R. Cui et al., “Design, synthesis and biological evaluation of cinnamic acid derivatives with synergetic neuroprotection and angiogenesis effect,” European Journal of Medicinal Chemistry, vol. 183, article 111695, 2019.

J. Zhang, X. Zhang, C. Wen, Y. Duan, and H. Zhang, “Lotus seedpod proanthocyanidins protect against neurotoxicity after methyl- mercuric chloride injury,” Ecotoxicology and Environmental Safety, vol. 183, article 109560, 2019.

Y. Ding, D. Kong, T. Zhou et al., “α-Arbutin protects against Parkinson's disease-associated mitochondrial dysfunction in vitro and in vivo,” Neuromolecular Medicine, vol. 22, no. 1, pp. 56–67, 2020.

A.-M. Krishna Chandran, H. Christina, S. Das, K.-D. Mumbrekar, and B.-S. Satish Rao, “Neuroprotective role of naringenin against methylmercury induced cognitive impairment and mitochondrial damage in a mouse model,” Environmental Toxicology and Pharmacology, vol. 71, article 103224, 2019.

F. Zhao, Y. Dang, R. Zhang et al., “Apigenin attenuates acrylonitrile-induced neuro-inflammation in rats: involved of inactivation of the TLR4/NF-κB signaling pathway,” International Immunopharmacology, vol. 75, article 105697, 2019.

Y. Jang, H. Choo, M. J. Lee et al., “Auraptene mitigates Parkinson's disease-like behavior by protecting inhibition of mitochondrial respiration and scavenging reactive oxygen species,” International Journal of Molecular Sciences, vol. 20, no. 14, p. 3409, 2019.

Y. Jin and H. Wang, “Naringenin inhibit the hydrogen peroxide-induced SH-SY5Y cells injury through Nrf 2/HO-1 pathway,” Neurotoxicity Research, vol. 36, no. 4, pp. 796–805, 2019.

P. Gupta, A. Singh, S. Tiwari, A. Mishra, R. Maurya, and S. Singh, “Ulmosides A: flavonoid 6-C-glycosides from ulmus wallichiana attenuates lipopolysacchride induced oxidative stress, apoptosis and neuronal death,” NeuroToxicology, vol. 73, pp. 100–111, 2019.

M.-W. Lin, C. C. Lin, Y.-H. Chen, H.-B. Yang, and S.-Y. Hung, “Celastrol inhibits dopaminergic neuronal death of Parkinson's disease through activating mitophagy,” Antioxidants, vol. 9, no. 1, p. 37, 2020.

O. Uličná, O. Vančová, J. Kucharská, P. Janega, and I. Waczulíková, “Rooibos tea (Aspalathus linearis) ameliorates the CCl4-induced injury to mitochondrial respiratory function and energy production in rat liver,” General Physiology and Biophysics, vol. 38, no. 1, pp. 15–25, 2019.

M. Rabenau, M. Unger, J. Drewe, and C. Culmsee, “Metabolic switch induced by Cimicifuga racemosa extract prevents mitochondrial damage and oxidative cell death,” Phytomedicine, vol. 52, pp. 107–116, 2019.

S. M. Park, S. W. Kim, E. H. Jung et al., “Sipjeondaebo-tang qlleviates oxidative stress-mediated liver injury through activation of the CaMKK2-AMPK signaling pathway,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 8609285, 13 pages, 2018.

X.-X. Yang, X. Wang, T.-T. Shi et al., “Mitochondrial dysfunction in high-fat diet-induced nonalcoholic fatty liver disease: The alleviating effect and its mechanism of Polygonatum kingianum,” Biomedicine & Pharmacotherapy, vol. 117, article 109083, 2019.

X. Zou, C. Yan, Y. Shi et al., “Mitochondrial dysfunction in obesity-associated nonalcoholic fatty liver disease: the protective effects of pomegranate with its active component punicalagin,” Antioxidants & Redox Signaling, vol. 21, no. 11, pp. 1557–1570, 2014.

M. Jung Kim, “Betaine enhances the cellular survival via mitochondrial fusion and fission factors, MFN2 and DRP1,” Animal Cells and Systems, vol. 22, no. 5, pp. 289–298, 2018.

S. Wang, T. Wan, M. Ye et al., “Nicotinamide riboside attenuates alcohol induced liver injuries via activation of SirT1/PGC-1α/mitochondrial biosynthesis pathway,” Redox Biology, vol. 17, pp. 89–98, 2018.

S. Wang, F.-J. Yang, L.-C. Shang, Y. H. Zhang, Y. Zhou, and X. L. Shi, “Puerarin protects against high-fat high-sucrose diet-induced non-alcoholic fatty liver disease by modulating PARP-1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis,” Phytotherapy Research, vol. 33, no. 9, pp. 2347–2359, 2019.

K. Fang, F. Wu, G. Chen et al., “Diosgenin ameliorates palmitic acid-induced lipid accumulation via AMPK/ACC/CPT-1A and SREBP-1c/FAS signaling pathways in LO2 cells,” BMC Complementary and Alternative Medicine, vol. 19, no. 1, p. 255, 2019.

G. Vecchione, E. Grasselli, F. Cioffi et al., “The nutraceutic silybin counteracts excess lipid accumulation and ongoing oxidative stress in an in vitro model of non-alcoholic fatty liver disease progression,” Frontiers in Nutrition, vol. 4, p. 42, 2017.

Y.-C. Wang, W.-Z. Kong, Q.-M. Jin, J. Chen, and L. Dong, “Effects of salvianolic acid B on liver mitochondria of rats with nonalcoholic steatohepatitis,” World Journal of Gastroenterology, vol. 21, no. 35, pp. s10104–s10112, 2015.

H.-K. Chung, Y.-K. Kim, J.-H. Park et al., “The indole derivative necrox-7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS/RNS and inflammation,” Liver International, vol. 35, no. 4, pp. 1341–1353, 2015.

Q. Hu, Q. Niu, H. Song et al., “Polysaccharides from Portulaca oleracea L. regulated insulin secretion in INS-1 cells through voltage-gated Na ⁺ channel,” Biomedicine & Pharmacotherapy, vol. 109, pp. 876–885, 2019.

J.-K. Park, J.-Y. Shim, A.-R. Cho, M.-R. Cho, and Y.-J. Lee, “Korean red ginseng protects against mitochondrial damage and intracellular inflammation in an animal model of type 2 diabetes mellitus,” Journal of Medicinal Food, vol. 21, no. 6, pp. 544–550, 2018.

M. Javadipour, M. Rezaei, E. Keshtzar, and M.-J. Khodayar, “Metformin in contrast to berberine reversed arsenic-induced oxidative stress in mitochondria from rat pancreas probably via Sirt3‐dependent pathway,” Journal of Biochemical and Molecular Toxicology, vol. 33, no. 9, 2019.

M.-J. Houghton, A. Kerimi, S. Tumova, J.-P. Boyle, and G. Williamson, “Quercetin preserves redox status and stimulates mitochondrial function in metabolically-stressed HepG2 cells,” Free Radical Biology & Medicine, vol. 129, pp. 296–309, 2018.

T. Tong, N. Ren, P. Soomi et al., “Theaflavins improve insulin sensitivity through regulating mitochondrial biosynthesis in palmitic acid-induced HepG2 cells,” Molecules, vol. 23, no. 12, p. 3382, 2018.

Y. Sun, J. Yang, W. Liu et al., “Attenuating effect of silibinin on palmitic acid-induced apoptosis and mitochondrial dysfunction in pancreatic β-cells is mediated by estrogen receptor alpha,” Molecular and Cellular Biochemistry, vol. 460, no. 1-2, pp. 81–92, 2019.

X.-F. Chen, L. Wang, Y.-Z. Wu et al., “Effect of puerarin in promoting fatty acid oxidation by increasing mitochondrial oxidative capacity and biogenesis in skeletal muscle in diabetic rats,” Nutrition & Diabetes, vol. 8, no. 1, 2018.

X. Wang, L. Zhao, A.-K. Ajay et al., “QiDiTangShen granules activate renal nutrient-sensing associated autophagy in db/db mice,” Frontiers in Physiology, vol. 10, p. 1224, 2019.

J. Tian, W. Tang, M. Xu et al., “Shengmai san alleviates diabetic cardiomyopathy through improvement of mitochondrial lipid metabolic disorder,” Cellular Physiology and Biochemistry, vol. 50, no. 5, pp. 1726–1739, 2018.

Y.-T. Tseng, W.-H. Chang, C.-C. Lin, F. R. Chang, P. C. Wu, and Y. C. Lo, “Protective effects of Liuwei Dihuang water extracts on diabetic muscle atrophy,” Phytomedicine, vol. 53, pp. 96–106, 2019.

J. Wei, H. Wu, H. Zhang et al., “Anthocyanins inhibit high glucose-induced renal tubular cell apoptosis caused by oxidative stress in db/db mice,” International Journal of Molecular Medicine, vol. 41, no. 3, pp. 1608–1618, 2018.

Z.-L. Kong, K. Che, J.-X. Hu et al., “Orientin protects podocytes from high glucose induced apoptosis through mitophagy,” Chemistry & Biodiversity, vol. 17, no. 3, article e1900647, 2020.

H. Xue, P. Li, Y. Luo et al., “Salidroside stimulates the Sirt1/PGC-1α axis and ameliorates diabetic nephropathy in mice,” Phytomedicine, vol. 54, pp. 240–247, 2019.

S. Sun, S. Yang, M. Dai et al., “The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells,” BMC Complementary and Alternative Medicine, vol. 17, no. 1, p. 310, 2017.

F. Nan, G. Sun, W. Xie et al., “Ginsenoside Rb1 mitigates oxidative stress and apoptosis induced by methylglyoxal in SH-SY5Y cells via the PI3K/Akt pathway,” Molecular and Cellular Probes, vol. 48, article 101469, 2019.

A. Zheng, H. Li, J. Xu et al., “Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: role of AMP-activated protein kinase activation,” The British Journal of Nutrition, vol. 113, no. 11, pp. 1667–1676, 2015.

L.-S. Lee, J.-H. Choi, M.-J. Sung et al., “Green tea changes serum and liver metabolomic profiles in mice with high-fat diet-induced obesity,” Molecular Nutrition & Food Research, vol. 59, no. 4, pp. 784–794, 2015.

S. Seo, S.-M. Jo, J. Kim, M. Lee, Y. Lee, and I. Kang, “Peanut sprout extracts attenuate triglyceride accumulation by promoting mitochondrial fatty acid oxidation in adipocytes,” International Journal of Molecular Sciences, vol. 20, no. 5, p. 1216, 2019.

T. Yoneshiro, R. Kaede, K. Nagaya et al., “Melinjo (Gnetum gnemon L) seed extract induces uncoupling protein 1 expression in brown fat and protects mice against diet-induced obesity, inflammation, and insulin resistance,” Nutrition Research, vol. 58, pp. 17–25, 2018.

M.-Y. Song, S.-Y. Kang, A. Kang, J. H. Hwang, Y. K. Park, and H. W. Jung, “Cinnamomum cassia Prevents high-fat diet-induced obesity in mice through the increase of muscle energy,” The American Journal of Chinese Medicine, vol. 45, no. 5, pp. 1017–1031, 2017.

N.-D.-S. Lima, L. Teixeira, A. Gambero, and M.-L. Ribeiro, “Guarana (Paullinia cupana) stimulates mitochondrial biogenesis in mice fed high-fat diet,” Nutrients, vol. 10, no. 2, 2018.

M.-S. Lee and Y. Kim, “Effects of isorhamnetin on adipocyte mitochondrial biogenesis and AMPK activation,” Molecules, vol. 23, no. 8, p. 1853, 2018.

M. Liu, M. Zheng, D. Cai et al., “Zeaxanthin promotes mitochondrial biogenesis and adipocyte browningviaAMPKα1 activation,” Food & Function, vol. 10, no. 4, pp. 2221–2233, 2019.

Y. Sun, C. Jin, X. Zhang, W. Jia, J. le, and J. Ye, “Restoration of GLP-1 secretion by berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice,” Nutrition & Diabetes, vol. 8, no. 1, p. 53, 2018.

W. Nam, S.-H. Nam, S.-P. Kim, C. Levin, and M. Friedman, “Anti-adipogenic and anti-obesity activities of purpurin in 3T3-L1 preadipocyte cells and in mice fed a high-fat diet,” BMC Complementary and Alternative Medicine, vol. 19, no. 1, p. 364, 2019.

M.-S. Lee, Y. Shin, S. Jung, and Y. Kim, “Effects of epigallocatechin-3-gallate on thermogenesis and mitochondrial biogenesis in brown adipose tissues of diet-induced obese mice,” Food & Nutrition Research, vol. 61, no. 1, article 1325307, 2017.

A. Braik, M. Lahouel, R. Merabe, M.-R. Djebar, and D. Morin, “Myocardial protection by propolis during prolonged hypothermic preservation,” Cryobiology, vol. 88, pp. 29–37, 2019.

J. Huang, Z. Liu, P. Xu et al., “Capsaicin prevents mitochondrial damage, protects cardiomyocytes subjected to anoxia/reoxygenation injury mediated by 14-3-3η/Bcl-2,” European Journal of Pharmacology, vol. 819, pp. 43–50, 2018.

X. Chen, X. Peng, Y. Luo et al., “Quercetin protects cardiomyocytes against doxorubicin-induced toxicity by suppressing oxidative stress and improving mitochondrial function via 14-3-3γ,” Toxicology Mechanisms and Methods, vol. 29, no. 5, pp. 344–354, 2019.

Z. Liu, L. Yang, J. Huang et al., “Luteoloside attenuates anoxia/reoxygenation-induced cardiomyocytes injury via mitochondrial pathway mediated by 14-3-3η protein,” Phytotherapy Research, vol. 32, no. 6, pp. 1126–1134, 2018.

Y. Luo, Q. Wan, M. Xu et al., “Nutritional preconditioning induced by astragaloside IV on isolated hearts and cardiomyocytes against myocardial ischemia injury via improving Bcl-2-mediated mitochondrial function,” Chemico-Biological Interactions, vol. 309, article 108723, 2019.

Y. Xie, R. Ji, and M. Han, “Eriodictyol protects H9c2 cardiomyocytes against the injury induced by hypoxia/reoxygenation by improving the dysfunction of mitochondria,” Experimental and Therapeutic Medicine, vol. 17, no. 1, pp. 551–557, 2019.

L. Wei, X. Sun, X. Qi, Y. Zhang, Y. Li, and Y. Xu, “Dihydromyricetin ameliorates cardiac ischemia/reperfusion injury through Sirt3 activation,” Bio Med Research International, vol. 2019, article 6803943, pp. 1–9, 2019.

W. Xue, X. Wang, H. Tang et al., “Vitexin attenuates myocardial ischemia/reperfusion injury in rats by regulating mitochondrial dysfunction induced by mitochondrial dynamics imbalance,” Biomedicine & Pharmacotherapy, vol. 124, article 109849, 2020.

Z. Tan, H. Liu, X. Song et al., “Honokiol post-treatment ameliorates myocardial ischemia/reperfusion injury by enhancing autophagic flux and reducing intracellular ROS production,” Chemico-Biological Interactions, vol. 307, pp. 82–90, 2019.

H. Huang, S. Lai, Y. Luo et al., “Nutritional preconditioning of apigenin alleviates myocardial ischemia/reperfusion injury via the mitochondrial pathway mediated by notch1/hes1,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 7973098, 15 pages, 2019.