Remedying the Mitochondria to Cure Human Diseases by Natural Products

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.


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 dis-orders, 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.

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.

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 identi-fied 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.
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.

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 tRNA Leu(UUR) gene is the most common cause of mitochondrial diabetes 2 Oxidative Medicine and Cellular Longevity    [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.

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).

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.

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 mitochondriainvolved 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.

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. 6 Oxidative Medicine and Cellular Longevity    Oxidative Medicine and Cellular Longevity Table  6: Antiobesity activity of natural products.
Types of nature products Natural products

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.  14 Oxidative Medicine and Cellular Longevity