Current Drug Targets (v.12, #6)
Editorial [Hot Topic: Mitochondria as a Drug Target in Health and Disease (Guest Editor: Paulo J. Oliveira)] by Paulo J. Oliveira (761-761).
The breath of life that runs inside our cells starts within mitochondria. In fact, complex life without mitochondria would notbe possible due to the multitude of functions in which these organelles participate. From the production of energy, to the controlof cell death pathways (yes, what feeds you can also kill you), calcium homeostasis, intracellular signaling and intermediatemetabolism, mitochondria are remarkable dynamic structures, with an important, yet undesirable, role as mediator of severaldisease processes. Moreover, mitochondria are also involved in the toxicity of several xenobiotics, which are known to causeharm to humans and interestingly, several idiosyncratic drug reactions are known to be mediated, at least in part bymitochondrial toxicity. It is of course expected that drug or disease-induced mitochondrial dysfunction will impact more organswith higher energy requirements, such as the cardiac and skeletal muscles and the central nervous system. If mitochondrialdysfunction can contribute to organ degeneration, then aiming at the protection of mitochondrial function should be a priority torescue 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 targetmitochondria, which provide the basis for their pharmacological and/or toxicity effects. The dual role of mitochondria in drugeffects is the objective of this special edition of Current Drug Targets entitled “Mitochondria as a Drug Target in Health andDisease”. Thirteen nicely done papers compose this special edition, written by well-known researchers in the field ofmitochondrial toxicology and disease. Different topics are covered in this special issue including a) the description of multipletechniques that can be used to derive instructive functional indicators of neuronal mitochondrial function and damage, b) therole of mitochondrial testing in drug development and safety, c) induction of mild mitochondrial membrane potentialuncoupling as a therapeutic strategy, d) the role of mitophagy in neurodegeneration during health and disease, e) use ofmitochondrial-directed agents to prevent dysfunction and reverse disease, f) mitochondrial tolerance to drugs and toxic agentsin ageing and disease, g) the alkaloid berberine as a possible anti-cancer mitochondrial-mediated agent, h) mitochondria as atarget for exercise-induced cardioprotection, i) the role of mitochondrial dynamics and biogenesis in metabolic syndrome, j) therole of mitochondria in the pathogenesis of liver diseases, k) targeting the mitochondrial adenine nucleotide translocator 2during 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.
Techniques to Investigate Neuronal Mitochondrial Function and its Pharmacological Modulation by Jorge M.A. Oliveira (762-773).
Mitochondria are central regulators of neuronal homeostasis and survival, and increasingly viewed as a drugtarget in several acute and chronic neurological disorders, e.g. stroke, Alzheimer's, Parkinson's, and Huntington'sdiseases. Frequent working hypotheses aim to establish whether and how chemical or genetic lesions affect mitochondrialfunction 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 fullyquantified by any single available technique. This review aims to provide a broad perspective on the roles played byneuronal 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 ofmitochondrial 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.
Investigating Mitochondrial Dysfunction to Increase Drug Safety in the Pharmaceutical Industry by Sashi Nadanaciva, Yvonne Will (774-782).
Drug-induced mitochondrial dysfunction is a contributor to both late-stage compound attrition and post-marketdrug withdrawals. This review outlines the mechanisms which lead to drug-induced mitochondrial dysfunction anddiscusses the tremendous advances that have been made in the development of in vitro methods to identify mitochondrialimpairment. Potentially useful animal models and in vivo methods to detect drug-induced mitochondrial impairment arealso discussed.
Mild Mitochondrial Uncoupling as a Therapeutic Strategy by Fernanda M. Cunha, Camille C. Caldeira da Silva, Fernanda M. Cerqueira, Alicia J. Kowaltowski (783-789).
Mild mitochondrial uncoupling, or the reduction of the efficiency of energy conversion without compromisingintracellular high energy phosphate levels, is a protective therapeutic strategy under many laboratory conditions. Here wediscuss these conditions, which include both cell and animal models of ischemia reperfusion and complications associatedwith the metabolic syndrome. We also discuss drugs that promote mild mitochondrial uncoupling and naturally occurringmild mitochondrial uncoupling pathways involving free fatty acid cycling and K+ transport.
Mitophagy in Neurodegeneration: An Opportunity for Therapy? by R.X. Santos, S.C. Correia, C. Carvalho, S. Cardoso, M.S. Santos, P.I. Moreira (790-799).
Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are characterized by distinctclinical manifestations and neuropathological hallmarks, but they also share common features like mitochondrialdysfunction. As strategic organelles in several cellular pathways, including life/death decision, it is crucial to maintain ahealthy mitochondrial pool to ensure cellular homeostasis. Macroautophagy is a pathway of lysosomal-dependentdegradation of cytosolic portions, such as misfolded proteins or damaged organelles. In the last decade this process hasgained new frontiers and is currently seen as a specific, rather than a random process. In this regard the term mitophagycame to describe the selective degradation of mitochondria by autophagy. This review is intended to discussmitochondrial dysfunction in Alzheimer's and Parkinson's diseases. The recent developments on the molecular basis ofmitophagy will be also argued. Finally, we will discuss mitophagy as a potential therapeutic target for neurodegenerativediseases.
Mitochondrial-Targeted Plastoquinone Derivatives. Effect on Senescence and Acute Age-Related Pathologies by M.V. Skulachev, Y.N. Antonenko, V.N. Anisimov, B.V. Chernyak, D.A. Cherepanov, V.A. Chistyakov, M.V. Egorov, N.G. Kolosova, G.A. Korshunova, K.G. Lyamzaev, E.Y. Plotnikov, V.A. Roginsky, A.Y. Savchenko, I.I. Severina, F.F. Severin, T.P. Shkurat, V.N. Tashlitsky, K.M. Shidlovsky, M.Y. Vyssokikh, A.A. Zamyatnin Jr, D.B. Zorov, V.P. Skulachev (800-826).
Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated withdecyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, isspecifically 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 antioxidantactivity of SkQ1H2. SkQ1H2 prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive toattack 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 -galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissuedamage 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 mitochondriamediatedapoptosis, an obligatory step of execution of programs responsible for both senescence and fast biochemicalsuicide of an organism after a severe metabolic crisis.
Mitochondrial Tolerance to Drugs and Toxic Agents in Ageing and Disease by Jan Suski, Magdalena Lebiedzinska, Nuno G. Machado, Paulo J. Oliveira, Paolo Pinton, Jerzy Duszynski, Mariusz R. Wieckowski (827-849).
Better understanding of the effect of ageing on mitochondrial metabolism and of the mechanisms of action ofvarious drugs is required to allow optimization of the treatment of many diseases with minimized risk of dangerousimpairment of mitochondrial function. Numerous reports show that efficacy of medical treatment depends on the age oftreated subjects. This applies particularly to the effect of drugs on various senescence-prone cellular pathways. In thisreview, we demonstrate how ageing affects various mitochondria-associated pathways and their response to a variety offactors. These factors include registered drugs and other chemicals, and account for diverse consequences which varydepending on the physiological condition. Pharmacological treatments aimed at improving mitochondrial function shouldthus have in mind the subject age.
Berberine as a Promising Safe Anti-Cancer Agent - Is there a Role for Mitochondria? by Catia V. Diogo, Nuno G. Machado, Ines A. Barbosa, Teresa L. Serafim, Ana Burgeiro, Paulo J. Oliveira (850-859).
Metabolic regulation is largely dependent on mitochondria, which play an important role in energyhomeostasis. Mitochondrial dysfunction results in an imbalanced energy supply to the cell, which may compromise itssurvival. Due to the role of mitochondrial factors/events in several apoptotic pathways, the possibility of targeting thatorganelle 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 formany centuries, especially in the traditional Chinese and Native American medicine. Several evidences suggest thatberberine possesses several therapeutic uses, including anti-tumoral activity. The present review supplies evidence thatberberine is a safe anti-cancer agent, exerting several effects on mitochondria, including inhibition of mitochondrialComplex I and interaction with the adenine nucleotide translocator which can explain several of the described effects ontumor cells.
Mitochondria as a Target for Exercise-Induced Cardioprotection by Antonio Ascensao, Jose Lumini-Oliveira, Paulo J. Oliveira, Jose Magalhaes (860-871).
Cardiac damage is a major contributor to the morbidity and mortality particularly associated with coronaryartery disease. Moreover, it is also related to some metabolic diseases such as diabetes and to some side effects of drugtreatments. 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 cardioprotectionagainst cardiac insults in both young and old animals. It is suggested that the beneficial effects resulting from increasedphysical 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 changesand include the up-regulation of mitochondrial chaperones, improved antioxidant capacity, and/or elevation of otherprotective molecules against cellular death. It is possible that under some conditions, exercise also diminishes theincreased susceptibility of cardiac mitochondria to undergo permeability transition pore opening through the modulationof 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, whichprovides biochemical, functional and morphological data illustrating the cross tolerance effect of exercise in theseconditions predisposing to cardiac mitotoxicity. However, further work should be addressed in order to clarify theprecise regulatory mechanisms by which physical exercise augments heart mitochondrial tolerance against manyconditions predisposing to dysfunction.
Regulation of Mitochondrial Biogenesis in Metabolic Syndrome by Anabela P. Rolo, Ana P. Gomes, Carlos M. Palmeira (872-878).
Insulin resistant individuals manifest multiple disturbances in free fatty acids metabolism and have excessivelipid accumulation in insulin-target tissues. A wide range of evidence suggests that defective muscle mitochondrialmetabolism, and subsequent impaired ability to oxidize fatty acids, may be a causative factor in the accumulation ofintramuscular lipid and the development of insulin resistance. Such mitochondrial dysfunction includes loss ofmitochondria, defects in the mitochondrial OXPHOS system and decreased rate of ATP synthesis. Stimulation ofmitochondrial biogenesis appears as a strategy for the clinical management of the metabolic syndrome, by enhancingmitochondrial activity and protecting the cell against the increased flux of reduced substrates to the electron transportchain and thus reducing metabolic inflammation.
Mitochondria in Chronic Liver Disease by Ignazio Grattagliano, Stefan Russmann, Catia Diogo, Leonilde Bonfrate, Paulo J. Oliveira, David Q.-H. Wang, Piero Portincasa (879-893).
Mitochondria are the main energy source in hepatocytes and play a major role in extensive oxidativemetabolism and normal function of the liver. This key role also assigns mitochondria a gateway function in the center ofsignaling pathways that mediate hepatocyte injury, because impaired mitochondrial functions affect cell survival andcontribute to the onset and perpetuation of liver diseases. Altered mitochondrial functions have indeed been documentedin a variety of chronic liver diseases including alcohol-induced liver disease, nonalcoholic fatty liver disease, viralhepatitis, primary and secondary cholestasis, hemochromatosis, and Wilson's disease. Major changes include impairmentof the electron transport chain and/or oxidative phosphorylation leading to decreased oxidative metabolism of varioussubstrates, decreased ATP synthesis, and reduced hepatocyte tolerance towards stressing insults. Functional impairment ofmitochondria is often accompanied by structural changes, resulting in organelle swelling and formation of inclusions inthe mitochondrial matrix. Adequate mitochondrial functions in hepatocytes are maintained by mitochondrial proliferationand/or increased activity of critical enzymes. The assessment of mitochondrial functions in vivo can be a useful tool inliver diseases for diagnostic and prognostic purposes, and also for the evaluation of (novel) therapeutic interventions.
The Adenine Nucleotide Translocase 2, a Mitochondrial Target for Anticancer Biotherapy by Ossama Sharaf el dein, Eleonore Mayola, Joel Chopineau, Catherine Brenner (894-901).
Apoptosis or programmed cell death is one of the most important signaling pathways, which controls the cellfate and is frequently impaired in cancer cells. The major consequences of apoptosis inhibition are the accumulation ofmutated cells and their enhanced resistance to chemotherapeutic agents. More generally, intrinsic or acquired apoptosisresistance may favor tumor growth and dissemination of mutated cells, and this resistance can be responsible of treatmentfailure. Mitochondria are central organelles in the signaling pathway of apoptosis and have been proposed as favoritecandidates for anticancer biotherapy because they accommodate potential biological targets. Indeed, although cancer cellsare highly glycolytic and become energetically independent of oxidative phosphorylation, mitochondrial proteins involvedin the so-called mitochondrial membrane permeabilization (MMP), such as the adenine nucleotide translocase (ANT) canbe instrumental to elicit cancer cell death. Thus, multiple pharmacological and molecular studies revealed ANT could be apromising therapeutic target for the following reasons: (i) ANT is a bi-functional protein, it mediates the vital exchange ofcytosolic ADP and mitochondrial ATP and participates to MMP via its capacity to become a lethal pore in themitochondrial inner membrane; (ii) both ANT functions are under the control of the (anti)-oncogenes from the Bax/Bcl-2family, (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 thisreview, we will introduce the knowledge of the role of ANT in MMP, illustrate the modulation of ANT by severalstrategies and propose the possibility to target preferentially the ANT2 isoform for induction of cancer cell apoptosis.
Repressing the Activity of Protein Kinase CK2 Releases the Brakes on Mitochondria-Mediated Apoptosis in Cancer Cells by Ismail Muhamad Hanif, Shazib Pervaiz (902-908).
Execution of the mitochondrial death signaling is paramount to an effective response of cancer cells tochemotherapeutic 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 mitochondrialpermeability, play a critical role in the acquisition of the resistant phenotype. Protein kinase CK2 (CK2) is a ubiquitousserine/threonine kinase that is highly conserved in eukaryotic cells. This multifunctional protein kinase has been shown toimpact 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 relevanceof CK2 biology to cellular transformation and carcinogenesis. Of note, among the many cellular substrates of CK2 areproteins 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 wellas pharmacological inhibition of its enzymatic activity sensitizes cancer cells to apoptotic stimuli. Due to the criticalregulatory role that this kinase plays in cell fate determination in cancer cells, there is a tremendous increase in activitygeared at the development of CK2-specific therapies. Here we provide a brief review of CK2-mediated inhibition ofmitochondrial death signaling in cancer cells and its implications for the design of novel target specific therapeuticstrategies.
The NK-1 Receptor: A New Target in Cancer Therapy by Miguel Munoz, Marisa Rosso, Rafael Covenas (909-921).
After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widelydistributed in both the central and peripheral nervous systems, induces tumor cell proliferation, angiogenesis, andmigration of the tumor cells for invasion and metastasis. However, after binding to NK-1 receptors, NK-1 receptorantagonists inhibit the three above mechanisms. In fact, the antiproliferative action exerted by NK-1 receptor antagonistsis because they induce cancer cells to die by apoptosis, whereas SP exerts an antiapoptotic effect. Moreover, it is knownthat NK-1 receptors are overexpressed in tumors and that tumor cells express several isoforms of the NK-1 receptor. Allthese data suggest that the SP/NK-1 receptor system could play an important role in the development of cancer; that SPmay be a universal mitogen in NK-1 receptor-expressing tumor cells, and that NK-1 receptor antagonists could offer apromising therapeutic strategy for the treatment of human cancer, since they act as broad-spectrum antitumor agents. Insum, the NK-1 receptor may be a new and promising target in the treatment of human cancer.
Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and New Therapeutic Perspectives in Non Small Cell Lung Cancer by Laura Bonanno, Antonio Jirillo, Adolfo Favaretto (922-933).
EGFR somatic mutations define a subset of NSCLCs that are most likely to benefit from EGFR tyrosine kinaseinhibitors (TKIs). These tumors are dependent on EGFR-signaling for survival. Recently, tyrosine kinase domain somaticmutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, allpatients ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary EGFR mutation in abouta half of patients. Uncontrolled activation of MET, another tyrosine kinase receptor, has been implicated in neoplasticinvasive growth. MET is overexpressed, activated and sometimes mutated in NSCLC cell lines and tumor tissues. METincreased gene copy number has also been documented in NSCLC and has been studied as negative prognostic factor. Ithas also been found in about 20% of patients developing acquired resistance to TKIs inhibitors. In this group, it seems todisplay 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. Differentmolecular alterations could be specifically targeted in order to extend disease control in this group of NSCLCs withdistinct clinical and molecular features. EGFR irreversible inhibitors, MET inhibitors and dual EGFR/VEGFR inhibitorsrepresent one of the most challenging issues in current clinical research. Ongoing clinical trials and future perspectives arediscussed.