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Advanced Drug Delivery Reviews (v.60, #13-14)

Editorial Board (pp. ii).

Mitochondrial medicine and mitochondrion-based therapeutics by Sarah Hamm-Alvarez Theme Editor; Enrique Cadenas Theme Editor (pp. 1437-1438).

Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases by Yuma Yamada; Hideyoshi Harashima (pp. 1439-1462).

Mitochondrial dysfunction has been implicated in a variety of human disorders—the so-called mitochondrial diseases. Therefore, the organelle is a promising therapeutic drug target. In this review, we describe the key role of mitochondria in living cells, a number of mitochondrial drug delivery systems and mitochondria-targeted therapeutic strategies. In particular, we discuss mitochondrial delivery of macromolecules, such as proteins and nucleic acids. The discussion of protein delivery is limited primarily to the mitochondrial import machinery. In the section on mitochondrial gene delivery and therapy, we discuss mitochondrial diseases caused by mutations in mitochondrial DNA, several gene delivery strategies and approaches to mitochondrial gene therapy. This review also summarizes our current efforts regarding liposome-based delivery system including use of a multifunctional envelope-type nano-device (MEND) and mitochondrial liposome-based delivery as anti-cancer therapies. Furthermore, we introduce the novel MITO-Porter—a liposome-based mitochondrial delivery system that functions using a membrane-fusion mechanism.

Keywords: Abbreviations; AAC; ATP/ADP carrier protein; ACE; angiotensin-converting enzyme; ACE-Cat; catalase conjugated with biotinylated anti-ACE antibody; ACE-SOD; CuZnSOD conjugated with biotinylated anti-ACE antibody; AIF; apoptosis-inducing factor; ANT; adenine nucleotide translocase; anti-PECAM/SOD; superoxide dismutases conjugated with anti-PECAM; Apaf-1; apoptotic protease activating factor-1; bp; base pair; Bmpr1a; bone morphogenetic protein receptor type 1 A; CM; cardiomyopathy; COS7 cells; cultured monkey kidney cells; CH; chaperone proteins; CPEO; chronic progressive external ophthalmoplegia; C/P molar ratio; condenser/protein molar ratio; CuZnSOD; copper–zinc-containing superoxide dismutases; cyt; c; cytochrome; c; DOPE; 1,2-dioleoyl-; sn; -glycero-3-phosphatidyl ethanolamine; DOPE-LP; liposome composed of DOPE; DQAplexes; DQAsomes–DNA complexes; EPC; egg yolk phosphatidyl choline; EPC-LP; liposome composed of EPC; ETC; electron transport chain; Exo III; exonuclease III protein; FRET; fluorescence resonance energy transfer; GFP; green fluorescent protein; GPx; glutathione peroxidase; IM; inner membrane; IMS; intermembrane space; INT-MTS; internal MTS; KSS; Kearns-Sayre syndrome; LHON; Leber's hereditary optic neuropathy; mtDNA; mitochondrial DNA; MELAS; myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MEND; multifunctional envelope-type nano-device; MEND (GFP); GFP-encapsulated in MEND; MERRF; myoclonic epilepsy with ragged-red fibers; MnSOD; manganese-containing superoxide dismutase; MP; mastoparan; MPP; mitochondrial processing peptidase; MTS; mitochondrial targeting signal peptide; MTS-ODN; MTS-conjugated ODN; NARP; neurogenic muscle weakness, ataxia, and retinitis pigmentosa; NLS; nuclear localization signal peptide; N-MTS; amino-terminal MTS; 3NP; 3-nitropropionic acid; ODN; oligodeoxynucleotides; OM; outer membrane; PAM; presequence translocase-associated motor; PECAM; platelet–endothelial cell adhesion molecule; PEG; polyethylene glycol; PLL; poly-; l; -lysine; PNA; peptide nucleic acid; PPD; PEG-Peptide-DOPE conjugate; PT; permeability transition; PTD; protein transduction domain; PTP; mitochondrial permeability transition pore; R8; octaarginine peptide; R8-MEND; MEND modified with high-density R8 peptide; R8-MEND (ODN); ODN-encapsulated in R8-MEND; R8-MEND (GFP); GFP-encapsulated in R8-MEND; R8-MEND (Protein); protein-encapsulated R8-MEND; RES; reticuloendothelial system; Rho; sulforhodamine B; ROS; reactive oxygen species; SA; stearylamine; SAM; sorting and assembly machinery; SS peptides; Szeto-Schiller peptides; STR-R8; stearyl R8; TAT; trans-activating transcriptional activator; TAT-mMDH-GFP; TAT-fusion protein that consisted of an MTS derived from mitochondrial malate dehydrogenase and green fluorescent protein; tBHP; t; -butylhydroperoxide; Tf; transferrin; Tf-GALA-LP; Tf-LP equipped with GALA; Tf-LP; transferrin-modified liposomes; TIM; translocator of the mitochondrial inner membrane; TCA cycle; tricarboxylic acid cycle; TOM; translocator of the mitochondrial outer membrane; TPP; triphenylphosphonium cations; VDAC; voltage-dependent anion channelMitochondria; Mitochondrial drug delivery; Mitochondrial macromolecule delivery; MITO-Porter; Membrane fusion; Multifunctional envelope-type nano-device (MEND); Mitochondrial protein therapy; Mitochondrial gene therapy; Mitochondrial protein import machinery; Mitochondrial DNA

Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease by Annette Maczurek; Klaus Hager; Marlene Kenklies; Matt Sharman; Ralph Martins; Jürgen Engel; David A. Carlson; Munch Gerald Münch (pp. 1463-1470).

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment – particularly for the early stages of disease – remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, LA has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. In addition, LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF and inducible nitric oxide synthase. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. In human plasma, LA exists in an equilibrium of free and plasma protein bound form. Up to 150 μM, it is bound completely, most likely binding to high affinity fatty acid sites on human serum albumin, suggesting that one large dose rather than continuous low doses (as provided by “slow release” LA) will be beneficial for delivery of LA to the brain. Evidence for a clinical benefit for LA in dementia is yet limited. There are only two published studies, in which 600 mg LA was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. Whereas the improvement in patients with moderate dementia was not significant, the disease progressed extremely slowly (change in ADAScog: 1.2 points=year, MMSE: −0.6 points=year) in patients with mild dementia (ADAScog<15). Data from cell culture and animal models suggest that LA could be combined with nutraceuticals such as curcumin, (−)-epigallocatechin gallate (from green tea) and docosahexaenoic acid (from fish oil) to synergistically decrease oxidative stress, inflammation, Aβ levels and Aβ plaque load and thus provide a combined benefit in the treatment of AD.

Keywords: Dementia; Treatment; Lipoic acid; Nutraceuticals; Antioxidant; Anti-inflammatory drug

Mitochondrial-mediated suppression of ROS production upon exposure of neurons to lethal stress: Mitochondrial targeted preconditioning by David W. Busija; Tamas Gaspar; Ferenc Domoki; Prasad V. Katakam; Ferenc Bari (pp. 1471-1477).

Preconditioning represents the condition where transient exposure of cells to an initiating event leads to protection against subsequent, potentially lethal stimuli. Recent studies have established that mitochondrial-centered mechanisms are important mediators in promoting development of the preconditioning response. However, many details concerning these mechanisms are unclear. The purpose of this review is to describe the initiating and subsequent intracellular events involving mitochondria which can lead to neuronal preconditioning. These mitochondrial specific targets include: 1) potassium channels located on the inner mitochondrial membrane; 2) respiratory chain enzymes; and 3) oxidative phosphorylation. Following activation of mitochondrial ATP-sensitive potassium (mitoK_ATP) channels and/or increased production of reactive oxygen species (ROS) resulting from the disruption of the respiratory chain or during energy substrate deprivation, morphological changes or signaling events involving protein kinases confer immediate or delayed preconditioning on neurons that will allow them to survive otherwise lethal insults. While the mechanisms involved are not known with certainty, the results of preconditioning are the enhanced neuronal viability, the attenuated influx of intracellular calcium, the reduced availability of ROS, the suppression of apoptosis, and the maintenance of ATP levels during and following stress.

Keywords: Abbreviations; Ca; ²⁺; calcium; ADP; adenosine di-phosophate; ATP; adenosine tri-phosphate; PKC; protein kinase C; Gsk3β; glycogen synthase kinase 3 beta; PI3K; phosphoinositide 3-kinase; Bad; Bcl-2 associated death promoter; NO; nitric oxide.Anoxia; Oxygen glucose deprivation; Ischemia; Brain; Mitochondria; ATP-sensitive potassium channels; Excitotoxicity; Necrosis; Apoptosis

Role of dichloroacetate in the treatment of genetic mitochondrial diseases by Peter W. Stacpoole; Tracie L. Kurtz; Zongchao Han; Taimour Langaee (pp. 1478-1487).

Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is metabolized by and inhibits the bifunctional zeta-1 family isoform of glutathione transferase/maleylacetoacetate isomerase. Polymorphic variants of this enzyme differ in their kinetic properties toward DCA, thereby influencing its biotransformation and toxicity, both of which are also influenced by subject age. Results from open label studies and controlled clinical trials suggest chronic oral DCA is generally well-tolerated by young children and may be particularly effective in patients with PDH deficiency. Recent in vitro data indicate that a combined DCA and gene therapy approach may also hold promise for the treatment of this devastating condition.

Keywords: Dichloroacetate; Mitochondria; Pyruvate dehydrogenase; Gene therapy; Pharmacogenetics; Pharmacotoxicology; Drug metabolism

Mitochondrial trifunctional protein defects: Clinical implications and therapeutic approaches by R. Scott Rector; R. Mark Payne; Jamal A. Ibdah (pp. 1488-1496).

The mitochondrial trifunctional protein (MTP) is a heterotrimeric protein that consists of four α-subunits and four β-subunits and catalyzes three of the four chain-shortening reactions in the mitochondrial β-oxidation of long-chain fatty acids. Families with recessively inherited MTP defects display a spectrum of maternal and fetal phenotypes. Current management of patients with MTP defects include long-term dietary therapy of fasting avoidance, low-fat/high-carbohydrate diet with restriction of long-chain fatty acid intake and substitution with medium-chain fatty acids. These dietary approaches appear promising in the short-term, but the long-term outcome of patients treated with dietary intervention is largely unknown. Potential therapeutic approaches targeted at correcting the metabolic defect will be discussed. We will discuss the potential use of protein transduction domains that cross the mitochondrial membranes for the treatment of mitochondrial disorders. In addition, we discuss the phenotypes of MTP in a heterozygous state and potential ways to intervene to increase hepatic fatty acid oxidative capacity.

Keywords: Fatty acids; β-oxidation; Mitochondrial trifunctional protein; LCHAD; Mitochondria; TAT; PTD; Fusion proteins; Protein transduction domain; Cell penetrant peptide

Monitoring oxidative and nitrative modification of cellular proteins; a paradigm for identifying key disease related markers of oxidative stress by James Murray; C. Elisa Oquendo; John H. Willis; Michael F. Marusich; Roderick A. Capaldi (pp. 1497-1503).

High levels of free radicals produced by the mitochondrial respiratory chain, with subsequent damage to mitochondria have been implicated in a large and growing number of diseases. The underlying pathology of these diseases is oxidative damage to mitochondrial DNA, lipids and proteins which accumulate over time to produce a metabolic deficiency. We are developing an antibody based immunocapture array for many important mitochondrial proteins involved in free radical production, detoxification and mitochondrial energy production. Our array is capable of a multi-parameter measurement including enzyme activity, quantity, and oxidative protein modifications. Here we demonstrate the use of this array by analyzing the proteomic differences in OXPHOS (oxidative phosphorylation) enzymes between human heart and liver tissues, cells grown in media promoting aerobic versus anaerobic metabolism, and the catalytic/proteomic effects of mitochondria exposed to oxidative stress. Protein oxidation is identified as carbonyl formation arising from reactive oxygen species and 3-nitrotyrosine as a marker of reactive nitrogen species. Several identified modifications are confirmed by electrophoresis and mass spectrometry of immunocaptured material. We continue to expand this array as antibodies for enzyme isolation and detection become available.

Keywords: Mitochondria; Oxidative stress; Proteomics; Modification; Antibody; Neurodegeneration

Estrogen regulation of glucose metabolism and mitochondrial function: Therapeutic implications for prevention of Alzheimer's disease by Roberta Diaz Brinton (pp. 1504-1511).

Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E₂ mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E₂ promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.

Keywords: Estrogen; Mitochondria; Bioenergetics; Aerobic glycolysis; Brain metabolism; Hormone therapy; Alzheimer's disease

Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astrocytes by Mei-Jie Jou (pp. 1512-1526).

Astrocytes, in addition to passively supporting neurons, have recently been shown to be actively involved in synaptic transmission and neurovascular coupling in the central nervous system (CNS). This review summarizes briefly our previous observations using fluorescent probes coupled with laser scanning digital imaging microscopy to visualize spatio-temporal alteration of mitochondrial reactive oxygen species (mROS) generation in intact astrocytes. mROS formation is enhanced by exogenous oxidants exposure, Ca²⁺ stress and endogenous pathological defect of mitochondrial respiratory complexes. In addition, mROS formation can be specifically stimulated by visible light or visible laser irradiation and can be augmented further by photodynamic coupling with photosensitizers, particularly with mitochondria-targeted photosensitizers. “Severe” oxidative insult often results in massive and homogeneous augmentation of mROS formation which causes cessation of mitochondrial movement, pathological fission and irreversible swelling of mitochondria and eventually apoptosis or necrosis of cells. Mitochondria-targeted antioxidants and protectors such as MitoQ, melatonin and nanoparticle C₆₀ effectively prevent “severe” mROS generation. Intriguingly, “minor” oxidative insults enhance heterogeneity of mROS and mitochondrial dynamics. “Minor” mROS formation-induced fission and fusion of mitochondria relocates mitochondrial network to form a mitochondria free gap, i.e., “firewall”, which may play a crucial role in mROS-mediated protective “preconditioning” by preventing propagation of mROS during oxidative insults. These mROS-targeted strategies for either enhancement or prevention of mitochondrial oxidative stress in astrocytes may provide new insights for future development of therapeutic interventions in the treatment of cancer such as astrocytomas and gliomas and astrocyte-associated neurodegeneration, mitochondrial diseases and aging.

Keywords: Antioxidant; Astrocyte; Mitochondrial dynamics; Mitochondrial reactive oxygen species; Preconditioning

Monoamine oxidase inactivation: From pathophysiology to therapeutics by Marco Bortolato; Kevin Chen; Jean C. Shih (pp. 1527-1533).

Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, β-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances.In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson's disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders.

Keywords: Monoamine oxidase; Depression; Parkinson's disease; Oxidative stress

Mitochondrial nitric oxide synthase, mitochondrial brain dysfunction in aging, and mitochondria-targeted antioxidants by Ana Navarro; Alberto Boveris (pp. 1534-1544).

This paper reviews the current ideas on nitric oxide (NO) physiology in brain and other mammalian organs and on the subcellular distribution of nitric oxide synthases (NOS) emphasizing on the evidence of a mitochondrial NOS isoform (mtNOS) that exhibits a mean activity of 0.86±0.09 nmol NO/min×mg protein in 13 mouse and rat organs. Mammalian brain aging is associated with mitochondrial dysfunction, determined as decreased electron transfer and enzymatic activities and as an increased content of phospholipid oxidation products and of protein oxidation/nitration products. Brain mtNOS is the most decreased enzymatic activity upon aging; decreased levels of NO are interpreted as the cause of decreased mitochondrial biogenesis in aged brain. The beneficial effect of high doses of vitamin E on mice survival and neurological function are related to its effect as antioxidant in brain mitochondria and to the preservation of mtNOS activity. Mitochondria-targeted antioxidants, phosphonium cation derivatives and antioxidant tetrapeptides, are reviewed in terms of structures and biological effects.

Keywords: mtNOS; NOS cellular distribution; Mitochondrial dysfunction; Brain aging; Vitamin E as antioxidant; Mitochondria-targeted antioxidants

Pro-oxidant shift in glutathione redox state during aging by Igor Rebrin; Rajindar S. Sohal (pp. 1545-1552).

The GSH:GSSG ratio, which is the primary determinant of the cellular redox state, becomes progressively more pro-oxidizing during the aging process due to an elevation in the GSSG content and a decline in the ability for de novo GSH biosynthesis. The K_m of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH biosynthesis, significantly increases during aging, which would adversely affect the ability for rapid GSH biosynthesis, especially under stressful conditions. Experimental studies suggest that age-related accumulation of homocysteine, an intermediate in the trans-sulfuration pathway, may be responsible for causing the loss of affinity between GCL and its substrates. Over-expression of GCL has been shown to prolong the life span of Drosophila by up to 50%, suggesting that perturbations in glutathione metabolism play a causal role in the aging process.

Keywords: Glutathione; Redox state; Redox potential; Glutathiolation; Mitochondria; Oxidative stress; Aging

Clinical implications of mitochondrial disease by Stanley Muravchick (pp. 1553-1560).

The terms mitochondrial myopathy, mitochondrial cytopathy and inherited mitochondrial encephalomyopathy encompass a large grouping of syndromes produced either by genetically transmitted or acquired disruption of mitochondrial energy production or biosensor function. Many of these disorders are clinically apparent during infancy, but for some the metabolic signs of oxidative stress may not appear until the young or middle adult years. Initially thought to be a rare disorder, it now appears that mitochondrial dysfunction is relatively common but often unrecognized because symptoms are extremely variable and usually insidious in onset. It has also become apparent that mitochondrial dysfunction is a component of many common cardiovascular and neurological disease states and of physiologic aging. Recent advances in our understanding of the mechanisms of mitochondrial dysfunction may explain and link a wide variety of clinical phenomena. This review summarizes the current knowledge regarding the clinical implications of inherited and acquired mitochondrial disease, the effects of anesthetics on mitochondrial function, and the extent to which mitochondrial bioenergetic state determines anesthetic requirement and potential anesthetic toxicity.

Keywords: Mitochondrial myopathy; Mitochondrial cytopathy; Inherited encephalomyopathy; Oxidative stress; Aging; Ischemic preconditioning; Anesthetic toxicity; Bioenergetics; Apoptosis

The mitochondrial cocktail: Rationale for combined nutraceutical therapy in mitochondrial cytopathies by M.A. Tarnopolsky (pp. 1561-1567).

Mitochondrial cytopathies ultimately lead to a reduction in aerobic energy transduction, depletion of alternative energy stores, increased oxidative stress, apoptosis and necrosis. Specific combinations of nutraceutical compounds can target many of the aforementioned biochemical pathways. Antioxidants combined with cofactors that can bypass specific electron transport chain defects and the provision of alternative energy sources represents a specific targeted strategy. To date, there has been only one randomized double-blind clinical trial using a combination nutraceutial therapy and it showed that the combination of creatine monohydrate, coenzyme Q10, and α-lipoic acid reduced lactate and markers of oxidative stress in patients with mitochondrial cytopathies. Future studies need to use larger numbers of patients with well defined clinical and surrogate marker outcomes to clarify the potential role for combination nutraceuticals (“mitochondrial cocktail”) as a therapy for mitochondrial cytopathies.

Keywords: Antioxidant; MELAS; LHON; Mitochondrial myopathy; Neuroprotection

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Advanced Drug Delivery Reviews (v.60, #13-14)