Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications - PubMed (original) (raw)
Review
Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications
Nadezda Apostolova et al. Antioxid Redox Signal. 2015.
Abstract
Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules.
Figures
**FIG. 1.
Representation of the involvement of mitochondria in health and disease. Mitochondria play a fundamental role in cell physiology; these organelles are involved in a variety of processes, including bioenergetics, various metabolic pathways, including crucial anabolic and catabolic reactions, such as ATP synthesis, the TCA cycle, and biosynthetic processes, and govern fundamental cellular actions, including proliferation, immunity, and autophagy. Mitochondrial damage and malfunction have been related to the pathogenesis of a large number of human pathologies, such as mitochondrial diseases, neurodegenerative diseases, cancer, cardiovascular diseases, metabolic disorders, and aging. The participation of mitochondria in the redox equilibrium and redox signaling of the cell is also pivotal. Modification of the redox state and increased ROS production within mitochondria have major consequences for both mitochondrial and extramitochondrial processes and, ultimately, modulate fundamental cellular phenomena such as autophagy and apoptosis. ROS, reactive oxygen species; TCA, tricarboxylic acid. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 2.
Mechanisms of oxidative stress involving mitochondria. (A) The mitochondrial ETC reoxidizes reduced cofactors (NADH and FADH2) using molecular oxygen as the final electron acceptor, and the energy released in this process is captured in the form of ATP. Several sites of the ETC (CI and CIII and the reverse electron flow at Complex II) generate O2•−. This radical is further converted into H2O2 by mitochondrial SOD. Other antioxidant enzymes within mitochondria involve TRX and GPX, and in certain tissues (liver, cardiac muscle) also CAT. Through the Fenton reaction, H2O2 is converted into •OH, a molecule that produces oxidative cell injury through DNA damage, carboxylation of proteins, and lipid peroxidation. Damaged mitochondria are dysfunctional and further produce free radicals, thus generating a “vicious cycle.” (B) Mechanisms of nitrosative stress. •NO is produced by the activity of intracellular NOS. •NO can be combined with O2•− to produce ONOO−, a molecule that acts as a strong oxidant and can damage many cellular structures and alter their function. Reactive nitrogen species such as ONOO− contribute to further mitochondrial dysfunction. •NO, nitric oxide; •OH, hydroxyl radical; CAT, catalase; ETC, electron transport chain; F, forward; GPX, glutathione peroxidase; H2O2, hydrogen peroxide; IMM, inner mitochondrial membrane; IMS, intermembrane space; NOS, nitric oxide synthase; O2•−, superoxide anion; ONOO−, peroxynitrite; OXPHOS, oxidative phosphorylation; R, reverse; SOD, superoxide dismutase; TRX, thioredoxin; Δψm, mitochondrial membrane potential. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 3.
Schematic representation of the process of mitochondrial dynamics (fission and fusion) and the proteins that regulate it. Fragmented mitochondria display features of mitochondrial dysfunction such as compromised OXPHOS, swelling, and induction of apoptosis. Oxidative stress is both an inducer and a consequence of mitochondrial fission. Increased ROS levels within the cell can result in mitochondrial fragmentation, which disrupts normal mitochondrial cycling. In turn, damaged and fragmented mitochondria generate increased amounts of ROS. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 4.
Mitochondrial implication in non-selective autophagy (bulk autophagy) and in selective mitochondrial removal through autophagy (mitophagy). The schematic diagram shows the implication of ROS in these processes. Oxidative stress in the cytoplasm triggers autophagy through several pathways. Oxidative stress in mitochondria together with other hallmarks of mitochondrial dysfunction (especially a drop in the mitochondrial membrane potential) induce selective degradation of mitochondria through a process called mitophagy. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 5.
The antioxidant machinery of a mammalian cell. Endogenous antioxidant defenses include enzymes and non-enzymatic small MW molecules. Many important antioxidants come from exogenous sources and can be delivered through the diet. MW, molecular weight.
**FIG. 6.
Structures of the salen Mn complexes EUK-189 and EUK-207. OAc acetoxy (CH3COO).
**FIG. 7.
Pharmacological characteristics of an “ideal” mitochondria-targeted antioxidant with clinical relevance. As a pharmaceutical agent, the mitochondria-targeted scavenger or redox-active molecule should be bioavailable, ideally on oral administration. After its absorption in plasma, it is delivered to target tissues (organs in which mitochondria play a prominent role, such as muscle, brain, or liver, are primary targets for treatment). The molecule readily enters the cell and accumulates inside mitochondria, where it ameliorates oxidative and nitrosative stress. BBB, blood brain barrier. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 8.
Available strategies for mitochondrial targeting. (A) Conjugates of lipophilic cations such as TPP and small molecules or nano-carriers exemplified by MitoQ (TPP-bound version of ubiquinol) and SkQ1H2 (plastoquinonyl decylTPP). (B) Targeting through mitochondria-specific bioactivation reactions, which catalyze the conversion of a prodrug to a drug. (C) Mitochondria-targeted peptides, including SS peptides and XJB peptides. (D) Actively transported mitochondrial antioxidants such as ergotheine. (E) DQAsomes—vesicle-like aggregates formed by the dicationic mitochondriotropic compound, dequalinium chloride. (F) Liposome-based carrier such as MITO-porter. MitoQ, mitoquinone; SkQ1, plastoquinonyl decyltriphenylphosphonium; SS, Szeto-Schiller; TPP, triphenylphosphonium. To see this illustration in color, the reader is referred to the web version of this article at
**FIG. 9.
Targeting compounds to mitochondria by conjugation to the lipophilic cation TPP. TPP has a large, hydrophobic surface area that enables it to pass easily through phospholipid bilayers. The molecule first passes through the plasma membrane and accumulates in the cytosol driven by the plasma membrane potential (Δψp). This strategy further utilizes the large Δψm (negative inside) to drive accumulation of TPP+-linked bioactive compounds inside mitochondria for several hundred fold. The antioxidant properties of the conjugates are exploited inside the mitochondrial compartment, and the oxidized forms are then re-reduced (recycled) by ETC complexes.
**FIG. 10.
Chemical structures of mitochondria-targeted antioxidants based on lipophilic cations: TPP+-conjugates (Mito compounds).
**FIG. 11.
Chemical structures of mitochondria-targeted antioxidants based on lipophilic cations: Sk-compounds.
**FIG. 12.
Chemical structures of peptide-based mitochondria-targeted antioxidants. (A) SS peptides. (B) XJP peptides.
**FIG. 13.
Stepwise schematic representation of the mitochondrial delivery of MITO-Porter encapsulated drugs. MITO-Porter enters cells via macropinocytosis, and its cytosolic delivery is enabled through the disruption of the macropinosome. Then, MITO-Porter is translocated to mitochondria via an electrostatic interaction of the MITO-Porter membrane component R8 with the mitochondrial membrane, and the liposomal cargo is delivered to mitochondria via mitochondrial membrane fusion. The lipid composition of MITO-Porter promotes both its fusion with the mitochondrial membrane and the release of its cargo into the intra-mitochondrial compartment.
**FIG. 14.
Chemical structures of TPP+-conjugated uncouplers: MitoBHT and MitoDNP. BHT, butylated hydroxytoluene; DNP, 2,4-dinitrophenol.
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