Current Pharmaceutical Design - Volume 17, Issue 20, 2011

Mitochondria have been in the focus of intense biomedical research over the last 10 years. The complex participation of these organelles in cellular pathophysiology arises from their versatile function which includes bioenergetics, ROS generation and redox balance, Ca2+ homeostasis maintainance, thermogenesis, essential anabolic pathways as well as active regulation of several cell survival/death pathways. Importantly, mitochondrial dysfunction such as impaired oxidative phosphorylation and/or increased oxidative stress, together with the involvement of these organelles in apoptosis and the alterations of the selective process of their degradation, known as mitophagy, have been recently described as essential pathophysiological mechanisms, involved not only in “classical” human mitochondrial diseases but also actively engaged in the initiation, the development and the out-come of other congenital and acquired pathologies such as diabetes [1], cancer [2], cardiovascular diseases [3] and neurodegenerative disorders [4]. Pharmacological agents with mitochondrial action and selective mitochondria-targeted drugs display major therapeutic potential. In the field of liver cancer, Muntane J and coll. (IMIBIC, “Reina Sofia” University Hospital, Cordoba, Spain) describe that several mitocans such as Hexokinase II inhibitors, ETC and VDAC/ANT-targeting drugs as well as BH3 mimetics can induce apoptosis through mitochondrial depolarization and thus exerting an anti-tumor effect [2]. Also, the inhibition of the glucose transport or glycolysis (fasentin, apigenin, the polyphenolic compounds WZB27 and WZB115) has been suggested as a promising anti-cancer treatment. Victor VM and coll. (University Hospital Doctor Peset Foundation and University of Valencia, Valencia, Spain) review the beneficial effects of mitochondrial modulation in diabetes and diabetes-related disorders such as diabetic kidney disease [1]. Mainly in vitro studies have proven useful several antioxidants such as idebenone (CoQ10 analogue), overexpression of antioxidant enzymes and small SOD mimetic molecules, however their beneficial effects have not always been reproduced in animal models or humans. There is evidence however, that selective targeting of mitochondria with specific compounds such as MitoQ, a mitochondriatargeted antioxidant, promises to be an efficient therapeutic strategy for mitochondrial protection in diabetes. In addition, mitochondriatargeted therapy is also relevant as a pharmacological approach for aging and neurodegenerative diseases such as Parkinsons's Disease, Alzheimer's disease and amyotrophic lateral sclerosis [4]. Serviddio G and coll. (Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy) review the effects of lipophilic cations such as MitoQ, MitoVitE and MitoPBN, Szeto-Schiller (SS) peptides, TAT fusion peptides and protein conjugates with mitochondria signal peptides (MSP). Novel mitochondria-targeted molecules such as XJB-5-131 and the multifunctional envelope-type nano-device (MEND) have also been described [4]. Two reviews of this thematic issue focus on mitochondrial turnover processes such as mitochondrial biogenesis and particularly mitophagy as novel/future avenues for pharmacological intervention [3,5]. Among other cardioprotective mitochondrial agents and stimuli, Gottlieb RA and coll. (BioScience Center, San Diego State University, San Diego, CA, USA) specifically point to caloric restriction, exercise and the use of resveratrol, a natural stilbenoid with antioxidant properties, as triggers of mitophagy and biogenesis [3]. Goldman SJ and Taylor R (Veterinary Support & Oversight Branch, U.S. Army Research Institute of Environmental Medicine, Natick, MA, USA) provide a detailed review of the cellular mechanisms involved in autophagy/mitophagy and their relation with the pathogenesis of neurodegeneration and cardiovascular diseases. Many of these conditions manifest accumulation of abnormal mitochondria and alterations in mitochondrial dynamics [5]. Our increasing understanding of the mitophagy-related diseases generates an expanding list of potential targets for pharmacological interventions which call to be explored. Mitochondrial therapeutics can also be relevant to the management of chronic parasitic infections exemplified in Chagas disease, a common trypanosomiasis. In a comprehensive review, Silber AM and coll. (Departament of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brasil) provide an insight into Trypanosoma cruzi mitochondria as drug targets [6]. The aminoacid metabolism has been given special emphasis. Several aminoacid-metabolizing enzymes such as arginine kinase and proline racemase as well some mitochondrial enzymes such as NADH-fumarate reductase have the potential to be specific targets in Chagas treatment as they have been indentified in the parasite but are absent in mammalian cells. T. cruzi also displays specificities regarding mitochondrial energetics and ROS generation which can be pharmacologically exploited. For instance, the fact that this parasite lacks catalase and peroxidase but possesses tryparedoxins, trypanothione and trypanothione reductase, homologues of which do not exist in the mammalian host, is an important issue in trypanoicidal drug engineering [6]. In summary, considering these very promising findings, it seems that modulation of mitochondrial function will be pursued in the novel therapeutic strategies designed to combat some of the current most common human diseases. On the other side, there is a rapidly growing list of drug-induced mitochondrial effects which can lead to the generation of severe drugrelated adverse events [7]. The interaction of drugs of clinical interest with specific mitochondrial targets and the repercussion of such interactions need to be evaluated in detail. This will certainly unable the prognosis and the treatment of a great number of drug-related detrimental reactions. Moreover, drug-induced mitotoxicity has been suggested to even contribute to the development of other mitochondriarelated pathologies. Several drug groups (anti-diabetic, lipid-lowering drugs, antiretrovirals, NSAID) have been attributed mitochondrial toxicity and this occurs through different mechanisms including interference with bionergetics, ROS generation, mitochondria-mediated apoptosis, mtDNA replication etc. This has been described by Nadanaciva S and Will Y (Compound Safety Prediction, Pfizer Global R&D, Groton, CT, USA) who also provide a thorough overview of the methodological and technical challenges in detection of drug-induced mitotoxicity [7]. Doxorubicin (DXR) is one of the most potent anti-cancer agents employed in clinical practice. Despite the fact that clinicians have been aware of its cardiotoxic effects for nearly 20 years now, DXR is still used. Oliveira PJ and coll. (Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal) delve in the complex mitochondrial role present in the cardiotoxic effects induced by this drug and provide some insights in the way that DXR-associated toxicity could be prevented or monitored. Finally, they also provide clues about the intriguing question regarding the organ-specificity of the toxic effect induced by DXR and its relation with other organs and tissues [8]. An interesting approach to combat drug-induced cardiac mitotoxicity is offered by the use of druginduced mitochondrial protection, as suggested for the non-selective β-blocker carvedilol. A beneficial outcome of such interaction has been shown in DXR-treated rats and some promising results have been obtained in human clinical trails [8]. A very complex mitochondrial implication has also been reported for the antiretroviral drugs applied in HIV treatment and this constitutes the origin of many clinically relevant adverse events related to this therapy, including myopathy, neuropathy, alterations in the lipid metabolism and hepatotoxicity. The review by Apostolova N and coll. (Faculty of Medicine, University of Valencia and CIBERehd, Valencia, Spain) scrutinizes the long list of mitochondrial mechanisms of interference associated with these drugs which includes besides the traditional target Pol-γ, the solely DNA polymerase responsible for mtDNA replication, several other, mtDNA-independent effects. One such interaction is the direct inhibitory action on ETC and the process of oxidative phosphorylation. These reactions are particularly important for protease inhibitors and NNRTI- groups of anti-HIV drugs which do not impair mtDNA replication and whose mitochondrial effects are largely unexplored [9]. In all, the intense and rapidly developing mitochondrial research has produced a new field of biomedical knowledge denominated “mitochondrial pharmacology”. Its present projection is to explore novel drug targets and drug-induced mechanisms of mitochondrial dysfunction in addition to dissecting the basic mitochondrial involvement in cellular pathogenic processes. All these findings have the final aim to generate models for successful mitochondrial therapeutic management.....

Diabetes is a severe, heterogeneous, multifactorial, chronic disease. Diabetes and oxidative stress are related to continuous and acute overproduction of reactive oxygen species (ROS). These ROS are released principally from mitochondria, but also have other sources. Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS are necessary for the proper functioning of the cell, but their excessive production can be harmful, making antioxidant defenses essential. Some substances with antioxidant properties, such as vitamins C and E, have been used to eradicate the oxidative stress associated with diabetes. The results of clinical trials employing anti-oxidative stress reagents in patients with diabetes are contradictory, perhaps due to inadequate study design or the specific targets selected. This review considers the process of diabetes from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or other molecules to mitochondria. The evidence compiled herein endorses the selective targeting of specific molecules to mitochondria as an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress.

Mitochondria are involved in different physiological and pathological processes that are crucial for tumor cell physiology, growth and survival. Since cancer cells have frequently disrupted different cell death pathways that promote their survival, mitochondria may be key organelles to promote cell death in cancer cells. The present review is focused on the different experimental and therapeutic cancer strategies addressed to either target mitochondria directly, or use mitochondria as mediators of apoptosis. While the first group includes drugs that act on glycolysis, β-oxidation, electron transport chain, mitochondrial permeability and the Bcl-2/IAP family protein, the second one consists of those drugs that cause cell death through the intrinsic apoptosis pathway by promoting ROS generation or by modulating mitochondrial protein involved in apoptosis induction.

Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function- however, they are also a potent source of free radicals and pro-apoptotic factors. As such, maintaining mitochondrial homeostasis is essential to cell survival. As the dominant source of ATP, continuous quality control is mandatory to ensure their ongoing optimal function. Mitochondrial quality control is accomplished by the dynamic interplay of fusion, fission, autophagy, and mitochondrial biogenesis. This review examines these processes in the heart and considers their role in the context of ischemia-reperfusion injury. Interventions that modulate mitochondrial turnover, including pharmacologic agents, exercise, and caloric restriction are discussed as a means to improve mitochondrial quality control, ameliorate cardiovascular dysfunction, and enhance longevity.

Aging is a physiologic state in which a progressive decline of organ functions may be accompanied by developing age-related diseases and neurodegenerative diseases. The causes of such conditions remain unknown, being probably related to a multifactor process. To date, the Free Radical and Mitochondrial theories seem to be the two most prominent that could explain both how and why aged people develop certain disorders, providing a rationale for treatment. Several reports demonstrate that mitochondria play a key role in aging and some neurodegenerative diseases. Damaged mitochondria produce increased amounts of Reactive Oxygen Species (ROS), leading, in turn, to progressive augmentation in damage. Dysfunctional mitochondria enhance susceptibility to cell death. Indeed, at cell level mitochondria act as an energetic hub determining cell final fate through caspase-dependent apoptosis. Thus, if aging results from oxidative stress, it may be corrected by environmental, nutritional and pharmacological strategies. In this review we summarize the role of mitochondria dysfunction occurring in aging and neurodegenerative disease, describing novel mitochondria-targeted therapy approach and the new selective molecules and nanocarriers technology as potentially effective in targeting mitochondrial dysfunction.

The process of intracellular macromolecular degradation known as macroautophagy has long been associated with the degradation of mitochondria. Recent studies have provided evidence that the process of mitochondria degradation via autophagy, now referred to as mitophagy, appears to be specifically targeted to mitochondria and highly regulated under both physiologic and pathologic conditions. This article provides a review of key developments in mitophagy research, including background information on the history, mechanisms, and regulation of macroautophagy, as well as discoveries that have enhanced our understanding of the specificity and independent regulation of mitophagy. This is followed by an analysis of how our current understanding of the mechanics and regulation of mitophagy may be exploited to yield pharmacological interventions for mitochondria-associated diseases. As yet, the potential for mitophagy- related pharmacological treatments for disease remains largely untapped. However, rapid progress in our understanding of both mitophagy and the pathology of mitochondria-related diseases is leading us towards the convergence of science and medicine which will inevitably result in new and potent pharmacological therapies for the treatment of these maladies.

Trypanosoma cruzi is the causative agent of Chagas' disease, which affects some 8 - 10 million people in the Americas. The only two drugs approved for the etiological treatment of the disease in humans were launched more than 40 years ago and have serious drawbacks. In the present work, we revisit the unique characteristics of T. cruzi mitochondria and mitochondrial metabolism. The possibility of taking advantage of these peculiarities to target new drugs against this parasite is also discussed.

Drug-induced mitochondrial toxicity is rapidly gaining recognition within the pharmaceutical industry as a contributor to compound attrition and post-market drug withdrawals. This article describes the mechanisms which lead to drug-induced mitochondrial toxicity, discusses high-throughput in vitro assays which are currently being used to identify mitochondrial dysfunction, and provides an overview on some of the drugs which impair mitochondrial function. While considerable progress has been made in the development of highthroughput assays to screen for mitochondrial impairment in vitro, much remains to be done. This includes the development of in silico models to predict drug-induced mitochondrial impairment, wider acceptance of suitable animal models, identification and validation of relevant biomarkers, and the translation of in vitro/in vivo results to clinical outcomes.

Mitochondria have long been involved in several cellular processes beyond its role in energy production. The importance of this organelle for cardiac tissue homeostasis has been greatly investigated and its impairment can lead to cell death and consequent organ failure. Several compounds have been described in the literature as having direct effects on cardiac mitochondria which can provide a mechanistic explanation for their toxicological or pharmacological effects. The present review describes one classic example of druginduced cardiac mitochondrial toxicity and another case of drug-induced mitochondrial protection. For the former, we present the case of doxorubicin, an anticancer agent whose treatment is associated with a cumulative and dose-dependent cardiomyopathy with a mitochondrial etiology. Following this, we present the case of carvedilol, a β-blocker with intrinsic antioxidant activity, which has been described to protect cardiac mitochondria from oxidative injury. The final part of the review integrates information from the previous chapters, demonstrating how carvedilol can contribute to reduce doxorubicin toxicity on cardiac mitochondria. The two referred examples result in important take-home messages: a) drug-induced cardiac mitochondrial dysfunction is an important contributor for drug-associated organ failure, b) protection of mitochondrial function is involved in the beneficial impact of some clinically-used drugs and c) a more accurate prediction of toxic vs. beneficial effects should be an important component of drug development by the pharmaceutical industry.

The combined antiretroviral therapeutic approach currently employed for the treatment of HIV infection, known as Highly Active Antiretroviral Therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, the adverse reactions associated with the long term use of this therapy have now become a major issue and researchers have focused on understanding the cellular mechanisms underlying these drug-induced detrimental effects which englobe a large list of different events including rash and hypersensibility reactions, hepatotoxicity, metabolic disturbances including lipodystrophy, and other metabolic syndrome-like disturbances such as hyperlactatemia, hyperlipedimia, insulin resistance and pancreatitis. Other events include CNS toxic effects, peripheral neuropathies as well as nephrotoxicity and increased risk of cardiovascular diseases. Many of these reactions have been shown to develop as a result of mitochondrial dysfunction. The mitochondrial effect of N(t)RTI (Nucleos( t)ide Reverse Transcriptase Inhibitors) class of drugs, which has been widely studied, is believed to originate from the inhibitory action of these drugs on DNA polymerase gamma, the enzyme responsible for replication of mitochondrial DNA. However, additional mitochondrial targets have also been described and need to be considered. As to NNRTI (Non-Nucleoside-Transcriptase Inhibitor) or PI (Protease Inhibitors), evidence of the implication of mitochondria has also been reported, however the details of the mechanisms underlying these actions are still not fully known. This review covers the current knowledge of mitochondrial toxicities, particularly the available in vitro evidence, regarding the most commonly used groups of HIV drugs. Novel findings of mtDNA-independent mitochondrial dysfunction have received special attention.