Current Drug Targets - Volume 12, Issue 6, 2011

The breath of life that runs inside our cells starts within mitochondria. In fact, complex life without mitochondria would not be possible due to the multitude of functions in which these organelles participate. From the production of energy, to the control of cell death pathways (yes, what feeds you can also kill you…), calcium homeostasis, intracellular signaling and intermediate metabolism, mitochondria are remarkable dynamic structures, with an important, yet undesirable, role as mediator of several disease processes. Moreover, mitochondria are also involved in the toxicity of several xenobiotics, which are known to cause harm to humans and interestingly, several idiosyncratic drug reactions are known to be mediated, at least in part by mitochondrial toxicity. It is of course expected that drug or disease-induced mitochondrial dysfunction will impact more organs with higher energy requirements, such as the cardiac and skeletal muscles and the central nervous system. If mitochondrial dysfunction can contribute to organ degeneration, then aiming at the protection of mitochondrial function should be a priority to rescue the affected organ, which is something that is easier said than done. Thus, it is clear that mitochondria are important drug targets in both health and disease. Several clinically used drugs target mitochondria, which provide the basis for their pharmacological and/or toxicity effects. The dual role of mitochondria in drug effects is the objective of this special edition of Current Drug Targets entitled “Mitochondria as a Drug Target in Health and Disease”. Thirteen nicely done papers compose this special edition, written by well-known researchers in the field of mitochondrial toxicology and disease. Different topics are covered in this special issue including a) the description of multiple techniques that can be used to derive instructive functional indicators of neuronal mitochondrial function and damage, b) the role of mitochondrial testing in drug development and safety, c) induction of mild mitochondrial membrane potential uncoupling as a therapeutic strategy, d) the role of mitophagy in neurodegeneration during health and disease, e) use of mitochondrial-directed agents to prevent dysfunction and reverse disease, f) mitochondrial tolerance to drugs and toxic agents in ageing and disease, g) the alkaloid berberine as a possible anti-cancer mitochondrial-mediated agent, h) mitochondria as a target for exercise-induced cardioprotection, i) the role of mitochondrial dynamics and biogenesis in metabolic syndrome, j) the role of mitochondria in the pathogenesis of liver diseases, k) targeting the mitochondrial adenine nucleotide translocator 2 during anti-cancer therapy and last but not least, l) the interplay between Casein Kinase II and mitochondrial-mediated apoptosis in cancer cells. It was a pleasure and an honor to be able to unite such outstanding pieces of work on our favorite organelle…mitochondria. Hope the reader agrees with me.

Mitochondria are central regulators of neuronal homeostasis and survival, and increasingly viewed as a drug target in several acute and chronic neurological disorders, e.g. stroke, Alzheimer's, Parkinson's, and Huntington's diseases. Frequent working hypotheses aim to establish whether and how chemical or genetic lesions affect mitochondrial function in neurons, and whether this can be rescued by pharmacological treatments. However, the generic designation ‘mitochondrial function’ actually encompasses a wide spectrum of individual activities, too numerous to be fully quantified by any single available technique. This review aims to provide a broad perspective on the roles played by neuronal mitochondria, and addresses multiple techniques that can be used to derive instructive functional indicators. These include measurements of mitochondrial respiration, ATP production, membrane potential, calcium handling, biogenesis, dynamic movement as well as fusion and fission. Technique descriptions are preceded by a summary of mitochondrial physiology and pharmacological tools required for functional modulation and parameter determination. Hopefully, these will assist researchers interested in testing mitochondria as a drug target in neurological disease models.

Drug-induced mitochondrial dysfunction is a contributor to both late-stage compound attrition and post-market drug withdrawals. This review outlines the mechanisms which lead to drug-induced mitochondrial dysfunction and discusses the tremendous advances that have been made in the development of in vitro methods to identify mitochondrial impairment. Potentially useful animal models and in vivo methods to detect drug-induced mitochondrial impairment are also discussed.

Mild mitochondrial uncoupling, or the reduction of the efficiency of energy conversion without compromising intracellular high energy phosphate levels, is a protective therapeutic strategy under many laboratory conditions. Here we discuss these conditions, which include both cell and animal models of ischemia reperfusion and complications associated with the metabolic syndrome. We also discuss drugs that promote mild mitochondrial uncoupling and naturally occurring mild mitochondrial uncoupling pathways involving free fatty acid cycling and K+ transport.

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are characterized by distinct clinical manifestations and neuropathological hallmarks, but they also share common features like mitochondrial dysfunction. As strategic organelles in several cellular pathways, including life/death decision, it is crucial to maintain a healthy mitochondrial pool to ensure cellular homeostasis. Macroautophagy is a pathway of lysosomal-dependent degradation of cytosolic portions, such as misfolded proteins or damaged organelles. In the last decade this process has gained new frontiers and is currently seen as a specific, rather than a random process. In this regard the term mitophagy came to describe the selective degradation of mitochondria by autophagy. This review is intended to discuss mitochondrial dysfunction in Alzheimer's and Parkinson's diseases. The recent developments on the molecular basis of mitophagy will be also argued. Finally, we will discuss mitophagy as a potential therapeutic target for neurodegenerative diseases.

Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H2 from its oxidized form that appears as a result of the antioxidant activity of SkQ1H2. SkQ1H2 prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H2O2-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondriamediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast “biochemical suicide” of an organism after a severe metabolic crisis.

Better understanding of the effect of ageing on mitochondrial metabolism and of the mechanisms of action of various drugs is required to allow optimization of the treatment of many diseases with minimized risk of dangerous impairment of mitochondrial function. Numerous reports show that efficacy of medical treatment depends on the age of treated subjects. This applies particularly to the effect of drugs on various senescence-prone cellular pathways. In this review, we demonstrate how ageing affects various mitochondria-associated pathways and their response to a variety of factors. These factors include registered drugs and other chemicals, and account for diverse consequences which vary depending on the physiological condition. Pharmacological treatments aimed at improving mitochondrial function should thus have in mind the subject age.

Metabolic regulation is largely dependent on mitochondria, which play an important role in energy homeostasis. Mitochondrial dysfunction results in an imbalanced energy supply to the cell, which may compromise its survival. Due to the role of mitochondrial factors/events in several apoptotic pathways, the possibility of targeting that organelle in the tumor cell, leading to its elimination is very attractive, although the safety issue is problematic. Berberine, a benzyl-tetra isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been extensively used for many centuries, especially in the traditional Chinese and Native American medicine. Several evidences suggest that berberine possesses several therapeutic uses, including anti-tumoral activity. The present review supplies evidence that berberine is a safe anti-cancer agent, exerting several effects on mitochondria, including inhibition of mitochondrial Complex I and interaction with the adenine nucleotide translocator which can explain several of the described effects on tumor cells.

Cardiac damage is a major contributor to the morbidity and mortality particularly associated with coronary artery disease. Moreover, it is also related to some metabolic diseases such as diabetes and to some side effects of drug treatments. Regular exercise has been confirmed as a pragmatic countermeasure to protect against cardiac injury. Specifically, life-long physical activity and endurance exercise training have been proven to provide cardioprotection against cardiac insults in both young and old animals. It is suggested that the beneficial effects resulting from increased physical activity levels occur at different levels of cellular organization, being mitochondria preferential target organelles. At present, it remains unclear what are the protective mechanisms that are essential for exercise-induced cardioprotection. Proposed mechanisms to explain the cardioprotective effects of exercise are mediated, at least partially, by redox changes and include the up-regulation of mitochondrial chaperones, improved antioxidant capacity, and/or elevation of other protective molecules against cellular death. It is possible that under some conditions, exercise also diminishes the increased susceptibility of cardiac mitochondria to undergo permeability transition pore opening through the modulation of pore components or sensitizers. The role of physical exercise against the impairment of heart mitochondrial function that accompany ageing, diabetes, administration of the anti-cancer agent Doxorubicin and ischemia-reperfusion is analysed in the present review, which provides biochemical, functional and morphological data illustrating the cross tolerance effect of exercise in these conditions predisposing to cardiac “mitotoxicity”. However, further work should be addressed in order to clarify the precise regulatory mechanisms by which physical exercise augments heart mitochondrial tolerance against many conditions predisposing to dysfunction.

Insulin resistant individuals manifest multiple disturbances in free fatty acids metabolism and have excessive lipid accumulation in insulin-target tissues. A wide range of evidence suggests that defective muscle mitochondrial metabolism, and subsequent impaired ability to oxidize fatty acids, may be a causative factor in the accumulation of intramuscular lipid and the development of insulin resistance. Such mitochondrial dysfunction includes loss of mitochondria, defects in the mitochondrial OXPHOS system and decreased rate of ATP synthesis. Stimulation of mitochondrial biogenesis appears as a strategy for the clinical management of the metabolic syndrome, by enhancing mitochondrial activity and protecting the cell against the increased flux of reduced substrates to the electron transport chain and thus reducing metabolic inflammation.

Mitochondria are the main energy source in hepatocytes and play a major role in extensive oxidative metabolism and normal function of the liver. This key role also assigns mitochondria a gateway function in the center of signaling pathways that mediate hepatocyte injury, because impaired mitochondrial functions affect cell survival and contribute to the onset and perpetuation of liver diseases. Altered mitochondrial functions have indeed been documented in a variety of chronic liver diseases including alcohol-induced liver disease, nonalcoholic fatty liver disease, viral hepatitis, primary and secondary cholestasis, hemochromatosis, and Wilson's disease. Major changes include impairment of the electron transport chain and/or oxidative phosphorylation leading to decreased oxidative metabolism of various substrates, decreased ATP synthesis, and reduced hepatocyte tolerance towards stressing insults. Functional impairment of mitochondria is often accompanied by structural changes, resulting in organelle swelling and formation of inclusions in the mitochondrial matrix. Adequate mitochondrial functions in hepatocytes are maintained by mitochondrial proliferation and/or increased activity of critical enzymes. The assessment of mitochondrial functions in vivo can be a useful tool in liver diseases for diagnostic and prognostic purposes, and also for the evaluation of (novel) therapeutic interventions.

Apoptosis or programmed cell death is one of the most important signaling pathways, which controls the cell fate and is frequently impaired in cancer cells. The major consequences of apoptosis inhibition are the accumulation of mutated cells and their enhanced resistance to chemotherapeutic agents. More generally, intrinsic or acquired apoptosis resistance may favor tumor growth and dissemination of mutated cells, and this resistance can be responsible of treatment failure. Mitochondria are central organelles in the signaling pathway of apoptosis and have been proposed as favorite candidates for anticancer biotherapy because they accommodate potential biological targets. Indeed, although cancer cells are highly glycolytic and become energetically independent of oxidative phosphorylation, mitochondrial proteins involved in the so-called mitochondrial membrane permeabilization (MMP), such as the adenine nucleotide translocase (ANT) can be instrumental to elicit cancer cell death. Thus, multiple pharmacological and molecular studies revealed ANT could be a promising therapeutic target for the following reasons: (i) ANT is a bi-functional protein, it mediates the vital exchange of cytosolic ADP and mitochondrial ATP and participates to MMP via its capacity to become a lethal pore in the mitochondrial inner membrane; (ii) both ANT functions are under the control of the (anti)-oncogenes from the Bax/Bcl-2 family, (iii) several chemotherapeutic agents directly modulate the pore-forming activity of ANT and (iv) ANT2 isoform, which is anti-apoptotic, can be overexpressed in human cancers and its invalidation sensitize cells to apoptosis. In this review, we will introduce the knowledge of the role of ANT in MMP, illustrate the modulation of ANT by several strategies and propose the possibility to target preferentially the ANT2 isoform for induction of cancer cell apoptosis.

Execution of the mitochondrial death signaling is paramount to an effective response of cancer cells to chemotherapeutic intervention. Therefore, factors that inhibit the engagement of the mitochondrial amplification pathway, such as the expression of the anti-apoptotic proteins of the Bcl2 family or inactivation of inducers of mitochondrial permeability, play a critical role in the acquisition of the resistant phenotype. Protein kinase CK2 (CK2) is a ubiquitous serine/threonine kinase that is highly conserved in eukaryotic cells. This multifunctional protein kinase has been shown to impact cell growth and proliferation, as numerous growth-related proteins are substrates of CK2. More importantly, experimental evidence linking increased expression and activity of the kinase to human cancers, underscores the relevance of CK2 biology to cellular transformation and carcinogenesis. Of note, among the many cellular substrates of CK2 are proteins involved in the efficient execution of the mitochondria-dependent cell death signaling, such as Bid, caspase-2, ARC and others. Supporting this, recent reports have demonstrated that genetic manipulation of CK2 expression as well as pharmacological inhibition of its enzymatic activity sensitizes cancer cells to apoptotic stimuli. Due to the critical regulatory role that this kinase plays in cell fate determination in cancer cells, there is a tremendous increase in activity geared at the development of CK2-specific therapies. Here we provide a brief review of CK2-mediated inhibition of mitochondrial death signaling in cancer cells and its implications for the design of novel target specific therapeutic strategies.

After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, induces tumor cell proliferation, angiogenesis, and migration of the tumor cells for invasion and metastasis. However, after binding to NK-1 receptors, NK-1 receptor antagonists inhibit the three above mechanisms. In fact, the antiproliferative action exerted by NK-1 receptor antagonists is because they induce cancer cells to die by apoptosis, whereas SP exerts an antiapoptotic effect. Moreover, it is known that NK-1 receptors are overexpressed in tumors and that tumor cells express several isoforms of the NK-1 receptor. All these data suggest that the SP/NK-1 receptor system could play an important role in the development of cancer; that SP may be a universal mitogen in NK-1 receptor-expressing tumor cells, and that NK-1 receptor antagonists could offer a promising therapeutic strategy for the treatment of human cancer, since they act as broad-spectrum antitumor agents. In sum, the NK-1 receptor may be a new and promising target in the treatment of human cancer.

EGFR somatic mutations define a subset of NSCLCs that are most likely to benefit from EGFR tyrosine kinase inhibitors (TKIs). These tumors are dependent on EGFR-signaling for survival. Recently, tyrosine kinase domain somatic mutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, all patients ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary EGFR mutation in about a half of patients. Uncontrolled activation of MET, another tyrosine kinase receptor, has been implicated in neoplastic invasive growth. MET is overexpressed, activated and sometimes mutated in NSCLC cell lines and tumor tissues. MET increased gene copy number has also been documented in NSCLC and has been studied as negative prognostic factor. It has also been found in about 20% of patients developing acquired resistance to TKIs inhibitors. In this group, it seems to display a new mechanism, which is able to mark tumor independence from EGFR signaling. The study of delayed resistance mechanisms could lead to the development of new therapeutic strategies. Different molecular alterations could be specifically targeted in order to extend disease control in this group of NSCLCs with distinct clinical and molecular features. EGFR irreversible inhibitors, MET inhibitors and dual EGFR/VEGFR inhibitors represent one of the most challenging issues in current clinical research. Ongoing clinical trials and future perspectives are discussed.