Mitochondria-Targeted Antioxidants: A Step towards Disease Treatment

Abstract

Mitochondria are the main organelles that produce adenosine 5${}^{\prime }$-triphosphate (ATP) and reactive oxygen species (ROS) in eukaryotic cells and meanwhile susceptible to oxidative damage. The irreversible oxidative damage in mitochondria has been implicated in various human diseases. Increasing evidence indicates the therapeutic potential of mitochondria-targeted antioxidants (MTAs) for oxidative damage-associated diseases. In this article, we introduce the advantageous properties of MTAs compared with the conventional (nontargeted) ones, review different mitochondria-targeted delivery systems and antioxidants, and summarize their experimental results for various disease treatments in different animal models and clinical trials. The combined evidence demonstrates that mitochondrial redox homeostasis is a potential target for disease treatment. Meanwhile, the limitations and prospects for exploiting MTAs are discussed, which might pave ways for further trial design and drug development.

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.

1. Introduction

Mitochondria, subcellular organelles found in most eukaryotic cells, are responsible for numerous metabolic network processes, including the tricarboxylic acid cycle (TCA cycle), glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, and fatty acid oxidation. Among them, the most important physiological function of mitochondria is to generate ATP by oxidizing nutrients. To participate in adenosine 5${}^{\prime }$-triphosphate (ATP) production, mitochondria use a complex system interacting with these metabolic network processes, during which free radicals are produced. Generally, mitochondrial ROS production mainly occurs at the site of the electron transport chain located on the mitochondrial inner membrane, and the leakage of electrons from complex I and complex III leads to oxygen consumption and superoxide formation [1]. The mitochondrial redox homeostasis refers to an equilibrium between ROS production and scavenging, which is the basis for mitochondrial function and cell fate determination [2].

At present, it is recognized that many pathological changes are associated with impaired mitochondrial function [3], such as increased accumulation of ROS and decreased OXPHOS and ATP production. Although the production of intracellular ROS is itself an inevitable process, cells have an adaptive defense system to scavenge ROS [4]. However, under most oxidative stress conditions, the endogenous antioxidant system in the cells is not enough to scavenge excess ROS. In that case, the accumulation of ROS will cause oxidative damage to intracellular lipids, DNA, and proteins, thereby accelerating the development of related diseases [5]. In the past decade, research has focused on maintaining redox homeostasis and normal function of mitochondria via antioxidants [6]. Current medical projects are aimed at exploiting drugs that restore mitochondrial function and regulate mitochondrial ROS production [7]. To modulate mitochondrial redox homeostasis, the drug should selectively accumulate in the mitochondria and interact with mitochondrial targets, ultimately maintaining normal cellular functions [8]. Although this mitochondrial targeting strategy is attractive, the clinical applications are hampered by some challenges, such as the poor biological availability and the lack of evidence in animal models and clinical research studies [9]. Several drugs have been applied for clinical trials; however, no drug has been approved by the US Food and Drug Administration (FDA) for mitochondria-targeted treatment.

The present review article is aimed at summarizing experimental data on mitochondria-targeted antioxidants (MTAs) for various disease treatments in different models and clinical trials to present the evidence supporting the therapeutic potential of these MTAs. We specifically focused on brain neurological diseases [10, 11], cardiovascular diseases [12–14], and cancer development [15, 16], all of which are closely associated with oxidative damage and signal activation caused by the excess accumulation of ROS in mitochondria. Meanwhile, the potential MTA applications in disease treatment, their limitations, and prospects for exploiting MTAs are discussed.

2. Moving Forward from Nontargeted Antioxidants to MTAs

An increasing number of studies are aimed at developing conventional (nontargeted) antioxidants for restoring physiology conditions during oxidative stress. Although preliminary studies on many cell or animal models showed promising results, the results from clinical trials were sometimes contradictory. A recent review article [17] has summarized the adverse effects of nontargeted antioxidants (NAs) including vitamin A, vitamin C, vitamin E, and β-carotene. These adverse effects of NAs were mainly observed in the treatments of lung cancer and cardiovascular diseases [18]. Redox signaling is an important part of many physiological processes. Excessive or inappropriate use of antioxidants may abolish ROS production and result in compensatory upregulation of mitogen-activated protein kinase (MAPK) pathways [19], which in turn negatively affect the endogenous antioxidant system and normal cell growth [20]. Another concern is whether conventional (nontargeted) antioxidants can be absorbed properly and how they are metabolized in different organs. These uncertainties make it difficult to determine the dose of traditional antioxidants used for disease treatment. The most effective way for an antioxidant stepping forward to disease treatment is to conjugate with a carrier, such as lipophilic cations, liposomes, or peptides, to enable its bioactive ingredient to be targeted for transport into the mitochondria. This targeted delivery enables antioxidants to achieve high concentration accumulation in cells and mitochondria, thereby protecting cells and tissues from oxidative damage through different mechanisms. Ideal antioxidants should be bioavailable and can quickly enter the blood circulation via intestinal absorption or intravenous injection. The MTAs could accumulate in the mitochondria and protect the targeted tissues (brain, liver, kidney, muscle, ear, and heart) from oxidative damage (Figure 1). In the past decade, many studies focusing on the development of mitochondria-targeted antioxidants gave promising results, which we will discuss in detail.

[figure omitted; refer to PDF]

Toxicity to mitochondria is a major limiting factor for the application of TPP-linked antioxidants in disease treatment [26]. During the transport of the TPP-linked antioxidants, TPPs increasingly adhere to the surface of the mitochondrial inner membrane. This accumulation of TPPs could destroy the integrity of the mitochondrial membrane and limit aerobic respiration and ATP synthesis [27]. In the toxicity assessment of in vivo experiments [28] using a mouse model, the maximum tolerated doses of methyl TPP and MitoE2 are 3.8 and 6.0 mg/($\text{kg}\ast \text{bodyweight}$), respectively. Evident toxic effects of TPP and MitoE2 were observed at 6.4 and 10.2 mg/($\text{kg}\ast \text{bodyweight}$), respectively. Intravenous injection of MitoQ was not toxic to the mice at 20 mg/($\text{kg}\ast \text{bodyweight}$) but significantly toxic at 27.0 mg/($\text{kg}\ast \text{bodyweight}$). It is noteworthy that long-term and low-dose MitoQ administration did not exhibit any toxic effect to the mouse models [29], which indicates that the toxic effect is caused by the disruption of normal function of mitochondria in response to a concentrated accumulation of TPP, and an oral administration with low-dose TPP compound is feasible. Therefore, in clinical trials testing TPP-linked antioxidants, it is necessary to strictly control the dosage and to ensure the effective concentration of the MTAs is lower than the threshold that destroys the normal function of mitochondria. Although some of these TPP-linked antioxidants such as MitoQ and SkQ1 have been evaluated in a wide range of clinical trials (NCT03166800, NCT02597023, NCT00329056, NCT03764735, and NCT02121301), more studies are required to assess their optimal dosages for different disease phases, their long-term effects on redox signal activation, and their potential side effects.

4. Liposome-Encapsulated Antioxidants

Liposomes are lipid bilayer membrane vesicles first discovered in 1964 and have been commonly used as nanocarriers for pharmaceuticals and bioactive substances [40]. One advantage of the liposomal encapsulation strategy over lipophilic cations is that bioactive molecules can be encapsulated and delivered without altering their molecular structure and bioactivity. The liposome-encapsulated antioxidants are composed of phosphatidylcholine, phosphatidylglycerol, cholesterol, and antioxidant component. The encapsulated antioxidants such as quercetin, N-acetyl-L-cysteine (NAC), and vitamin E exhibited better therapeutic effects on the models of liver injuries [41] and MCF-7 carcinoma cells [42] when compared with those in nonencapsulated form. For example, only liposomal encapsulated NAC can long-lastingly prevent the cytokine-induced neutrophil chemoattractant expression in the lung, thereby protecting the rats against lipopolysaccharide-induced acute respiratory distress syndrome [43]. It has been reviewed that liposomal encapsulated analogs of vitamin E (α-tocopheryl succinate and α-tocopheryl ether-linked acetic acid) exerted better anticancer effects on various cancer models due to their higher solubility in aqueous solvents [44]. In a clinical study on fatty liver patients, the phospholipid-encapsulated silybin was revealed to protect the liver from oxidative damage via enhancing mitochondrial function and insulin sensitization [45]. Liposome-encapsulated curcumin administration with 100 mg/($\text{kg}\ast \text{bodyweight}$) increased the parameters of plasma antioxidant activity in the Sprague-Dawley rat [46]. Likewise, astaxanthin encapsulated within liposomes showed a better bioavailability than the nonencapsulated astaxanthin and ameliorated oxidative parameters in the Sprague-Dawley rat model of lipopolysaccharide- (LPS-) induced acute hepatotoxicity [47].

Liposome-based delivery systems can carry conventional antioxidants into the mitochondria of the living cells. The transport mechanism of liposome-encapsulated MTAs is shown in Figure 3. Liposome-encapsulated antioxidants enter the cells via micropinocytosis; after macropinosome disruption, the liposomal components fuse with the mitochondrial membrane, during which the antioxidant components are delivered into the matrix of targeted mitochondria. The main disadvantage of the liposome system for MTA delivery is the escape of endosome degradation, which limits the endosomes spontaneously degrading in the cytoplasm and mitochondria. To overcome this limitation, the MITO-Porter that consists of a condensed plasmid DNA and a lipid envelope was developed to deliver bioactive components to mitochondria [48]. The inventors have introduced the characteristics and potential development of MITO-Porter in a specific chapter [49]. Generally, the MITO-Porter-decorated liposomes consist of 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine, sphingomyelin, and stearylated octaarginine peptide (R8). During a mitochondria-targeted delivery process, the MITO-Porter-decorated liposomes bind to the mitochondria via electrostatic interactions between R8 and negatively charged mitochondria and then fuse with the mitochondrial membrane. This delivery system can achieve efficient cytoplasmic and mitochondria-targeted delivery, which provides a new way for the treatment of mitochondrial disease. Besides, delivery experiments using fluorescent probes have verified MITO-Porter as an effective tool for macromolecule-targeted delivery [50].

[figure omitted; refer to PDF]

In a mouse model of liver ischemia/reperfusion injury, systemic injection of MITO-Porter-encapsulated CoQ10 (CoQ10-MITO-Porter) decreased serum alanine transaminase (ALT) and prevented kidney injury [51]. Recently, the mitochondrial delivery of methylated β-cyclodextrin-threaded polyrotaxanes using a MITO-Porter was revealed to mediate mitochondrial autophagy, which might be useful for mitochondria-associated disease treatment [52]. Moreover, the dual-function MITO-Porter (DF-MITO-Porter) that integrates both R8-modified liposomes and MITO-Porter was developed to effectively deliver exogenous macrobiomolecules into the mitochondria, providing an excellent delivery system for mitochondrial disease treatment [53]. More research studies on the MITO-Porter delivery system are expected to be conducted to shed more light on the mitochondrial therapeutic strategy and targeted antioxidant development.

5. Peptide-Based Mitochondrial Antioxidants

The Szeto-Schiller peptide (SS-peptide) and the mitochondria-penetrating peptide (MPP) are peptide chain-based antioxidant delivery systems. SS-peptides contain different small-molecule lipophilic antioxidant compounds and three positive charges and can be targeted-delivered to the mitochondria with the help of ΔΨm of the cellular membrane and mitochondrial membrane [54]. The advantageous properties of SS-peptides include the following: (1) alternating the MPP sequence between the basic and aromatic residues which favor their efficient absorption by cells; (2) unsaturated transport independently from the energy state or a dedicated peptide transporter [55]; (3) small and easily soluble in water, easy to synthesize, and the presence of D-amino acids at specific positions which prevents them from being degraded by aminopeptidases and allows them to be effectively transported into the mitochondria [56]; and (4) 1000-5000 times accumulation in the mitochondria.

Various experiments have confirmed that SS-peptides can be rapidly absorbed by different cell types, such as neurons [57], kidneys [58], epithelial cells, and endothelial cells [59]. It is noteworthy that the mitochondrial uptake speed of SS-peptides is ΔΨm-independent. The absorption of the SS-peptides does not affect the polarization of the mitochondrial membrane, which makes them ideal antioxidants for disease treatment [60]. For example, SS-02 was revealed to easily penetrate a single layer of intestinal epithelial cells from the basal and apical direction [61]. SS-02 has also been reported to penetrate the blood-brain barrier and thus serve as a neuroprotective agent [62]. The SS-peptides are effective in alleviating oxidative stress both in cell models and isolated mitochondria [63], among them SS-31 was widely validated to be effective. The therapeutic potential of SS-31 has been documented for many conditions including brain microvascular endothelial cell damage [64], lateral line hair cell damage [65], mitochondrial morphogenesis [66], atherosclerosis [67], Friedreich ataxia [68], renal fibrosis [69], limb ischemia-reperfusion injury [70], exercise tolerance [71], type 2 diabetes [72], hearing loss [73], neurovascular coupling responses [74], cardiac arrest [75], traumatic brain injury [76, 77], heart failure [78–81], and acute kidney injury [82]. Of importance, the phase 2a clinical trial of SS-31 (unique identifier: NCT01755858) on the atherosclerotic renal artery stenosis patients (ARASP) showed that supplementing with SS-31 during percutaneous transluminal renal angioplasty alleviated the pathological symptoms and improved kidney function, indicating a positive prospect of SS-31 in clinical application for ARASP [83].

A recent study on aged mice revealed that the disruption of mitochondrial redox homeostasis in muscle resulted in energy defect and exercise intolerance, and SS-31 administration restored redox homeostasis of the aged muscle, thereby increasing the exercise tolerance [71]. Five hours of SS-31 treatment significantly decreased mortality of cardiac arrest rats, during which the blood lactate level in the SS-31-treated rats was significantly decreased, suggesting improved mitochondrial aerobic respiration by SS-31 treatment [75]. The antioxidative roles of SS-31 have been also documented in kidney glomerular mitochondria [84]. SS-31 administration was revealed to prevent negative changes in pathological parameters in chronic kidney disease models [69]. More recently, an acute kidney injury- (AKI-) targeted nanopolyplex was designed for SS-31 delivery, which demonstrates a positive effect of combining the use of nanopolyplexes and SS-31 in the oxidative stressed and inflamed kidney [82]. Similarly, treatment with SS-31 was found to decrease cytoplasmic and mitochondrial O^2- production by regulating the expression of NADPH oxidase subunit NOX4 in a model of traumatic brain injury [76].

Mitochondria-penetrating peptides (MPPs) consist of 4 to 8 alternating positively charged hydrophobically modified amino acids. They have been widely used for the targeted delivery of mitochondrial small molecules with the help of ΔΨm [85]. A series of XJB peptide-based antioxidants (XJB-5-131, XJB-5-125, and XJB-5-197) have been developed (Figure 4). XJB-5-131, a scavenger for mitochondrial ROS, is the most studied among all the XJB peptide-based antioxidants and has been reported to promote weight gain, prevent neuronal death, and reduce oxidative damage in a mouse model of neurodegeneration [86]. Besides, XJB-5-131 was demonstrated to alleviate oxidative damage of DNA and improve physiology behavior in a Huntington’s disease model [87, 88]. Likewise, the compounds of XJB-5-131 and JP4-039 were reported to inhibit ferroptosis via scavenging ROS and altering the subcellular localization of the ferroptosis suppressors [89]. These findings encourage more therapeutic evaluation of XJB peptide-based antioxidants in clinical trials.

[figure omitted; refer to PDF]

MTAs have yielded promising results in several in vitro and animal models for cancer studies; however, it is noteworthy that some subsets of cancer cells, such as melanoma tumor cells, exhibit metabolic reprogramming heterogeneity, showing different bioenergy and ROS detoxification capabilities [147]. Besides, a study comparing the effects of MTAs and NAs on the hepatocarcinogenesis indicates contradictory results; that is, nontargeted antioxidants (NAC and vitamin E analog Trolox) prevented tumorigenesis, whereas MTAs (SS-31 and Mito-Q) aggravated tumorigenesis [148]. Therefore, it is critical to clarify the metabolic patterns of different cancer cells in a specific stage and to carefully adopt appropriate therapeutic strategies before clinical intervention with MTAs.

7. Conclusion

Mitochondria produce most of the energy and ROS in cells. Mitochondrial ROS are important signaling molecules involved in many cellular adaptative oxidative defense systems. However, excessive ROS accumulation or insufficient clearance results in damaged mitochondrial DNA and protein, both of which are pathophysiological features of a variety of diseases. In the past decades, many studies focused on developing NAs to restore the normal physiological function of oxidative stressed mitochondria. Research studies on various models were promising, but clinical trials sometimes showed contradictory results. Redox signaling is an important part of many physiological processes. Excessive or inappropriate use of antioxidants may abolish ROS production and result in compensatory upregulation of MAPK pathways, which in turn break down the endogenous antioxidant system. Thus, applying the appropriate dosage and delivery method of these antioxidants to balance ROS production and antioxidation is crucial for the clinical trials. Recently, a variety of mitochondria-targeted delivery systems and antioxidants have been exploited to recover mitochondrial function from the pathological conditions in different mechanisms. The outstanding advantages of MTAs over the nontargeted ones include (1) efficient pharmacokinetics and absorption and (2) specific accumulation at cells and mitochondria, avoiding nonspecific high concentration-induced side effects.

This article reviews the characteristics and applications of different mitochondria-targeting tools, including lipophilic cations, liposome vectors, peptide-based targeting, and their recent research reports. Overall, most of these tools have shown beneficial roles for mitochondria-targeting delivery. Based on these delivery tools, an increasing number of MTAs are currently being evaluated, some of which have been validated as effective agents in stage 2 clinical trials, providing unlimited possibilities for mitochondria-targeted therapies. Although the results from current studies are very promising, the human clinical trials on different disease stages should be firstly standardized to effectively translate these research results into usable medicines. Besides, these noteworthy questions should be preferentially considered to exploit more MTAs for disease treatment in the future (refer to noteworthy questions).

Additional Points

Noteworthy Questions. (1) What is the decisive mechanism in the development of mitochondria-targeted disease? (2) What is the most effective antioxidant for regulating the decisive mechanism (according to the experiment on separated mitochondria)? (3) Which delivery system will be the best choice for the mitochondria-targeted delivery of antioxidants? (4) How to optimize the effective MTA dosage in different administration approaches (e.g., oral, intravenous, or subcutaneous) for disease treatment? (5) How to standardize a clinical trial (e.g., how many patients to get involved, how long for patient tracking, and what parameters to assess side effects) for the evaluation of MTAs in disease treatment?

Authors’ Contributions

Q. J., J. Y., JS. C., XK. M., MM. W., G. L., K. Y., BE. T., and YL. Y. cowrote the manuscript.

Acknowledgments

The authors apologize to scientists in this field whose papers are not cited due to space limitations. The authors are grateful to Emily Ammeter, who is one of the summer undergraduate students in the Department of Animal Science at the University of Manitoba, for her help in the manuscript preparation. This research was funded by the Young Elite Scientists Sponsorship Program by CAST (2019QNRC001), the Hunan Science Foundation for Outstanding Young Scholars (2020JJ3023), and the Open Project Program of Key Laboratory of Feed Biotechnology, the Ministry of Agriculture and Rural Affairs of the People’s Republic of China.

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