Current Medicinal Chemistry (v.22, #20)

Meet Our Editorial Board Member by James David Adams (2405-2405).

Editorial (Thematic issue): Metabolic Diseases: Drugs and Mitochondrial Targets by Carlos M. Palmeira, Anabela P. Rolo (2406-2406).

Influence of Vanin-1 and Catalytic Products in Liver During Normal and Oxidative Stress Conditions by Daniel W. Ferreira, Philippe Naquet, Jose E. Manautou (2407-2416).
In liver, cysteamine in all probability represents a 'low-capacity, high-affinity' scavenger of ROS. The available body of evidence suggests that reduced cysteamine and oxidized cystamine exist in equilibrium and that this ratio acts as an active redox sensor within the cell much like GSH. During normal liver homeostasis cysteamine's antioxidant properties are evident. Highly metabolic and/or pro-oxidative conditions, such as in mice treated with peroxisome proliferators, shift this equilibrium to favor the oxidized form. Under these conditions, cystamine is likely able to inactivate proteins involved in energy biogenesis through cysteaminylation of critical Cys residues as has been shown in vitro. This would allow cystamine to function as a 'metabolic brake' to prevent the formation of additional ROS. In vivo, subcellular localization, pH, reducing capacity, FMO status and metabolic rate are all probable factors in determining the cysteamine:cystamine ratio. The availability of free cysteamine is also regulated by hydrolysis of pantetheine by pantetheinase. This cleavage results in the formation of pantothenic acid, a precursor to Coenzyme A which is prominently involved with lipid metabolism and energy production by the β -oxidation pathway and TCA cycle, respectively. Expression of pantetheinase is controlled by the Vnn1 gene and is upregulated in response to free fatty acids, PPAR activation or oxidative stress. The use of Vnn1 knockout mice has provided clear evidence that Vnn1 modulates redox and immune pathways In vivo, both of which appear at least partially due to a loss of cysteamine/cystamine. Immunologically, Vnn1 expression may influence cell signaling indirectly through maintenance of disulfide bonds or directly by interaction of pantetheinase on the cell surface. Cysteamine treatment has been used clinically as an antidote to APAP poisoning and in animal models against hepatotoxicants including APAP, galactosamine and CCl4. Protection in animal models occurs even when administered up to 12 hours following intoxication, suggesting that protection is the result of effects that occur downstream of bioactivation and covalent binding of reactive metabolites to target cellular macromolecules. Currently, the downstream influences of Vnn1 expression and cysteamine at endogenous concentrations remain largely unknown. Vnn1 knockout mice represent a valuable tool available to researchers investigating these events. Future studies in the field are needed to elucidate the precise mechanisms by which pantetheinase and/or cysteamine impact immune cell recruitment, cell signaling and survival, though it is clear that these factors have far reaching implications in the fields of immunology and toxicology.

Glycation and Hypoxia: Two Key Factors for Adipose Tissue Dysfunction by Paulo Matafome, Tiago Rodrigues, Raquel Seica (2417-2437).
Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. One of such aspects is certainly hypoxia, which was shown to develop in adipose tissue of obese individuals and animal models. Recent data suggest two main factors for adipose tissue hypoxia: adipocyte hypertrophy and vascular dysfunction. In addition, glycation was also shown to induce morphological and functional alterations in adipose tissue. In particular, methylglyoxal directly formed from glucose was shown to potently induce AGE formation in vivo and to contribute to metabolic and vascular alterations in adipose tissue. Glycation and hypoxia are both thought to be on the basis of low grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. This review summarizes the current knowledge about the factors that contribute for tissue hypoxia and the role of glycation, not only at the vascular level, but also at the metabolic, oxidative and inflammatory levels.

Shutting Down the Furnace: Preferential Killing of Cancer Cells with Mitochondrial-Targeting Molecules by Cláudia M. Deus, Gabriela L. Santos, Rute Loureiro, Ignacio Vega-Naredo, Henrique Faneca, Paulo J. Oliveira (2438-2457).
Mitochondria are organelles which play an important role not only in cellular metabolism but also in controlling pathways related with cell death, ionic and redox regulation. Alterations in mitochondrial metabolism are implicated in a variety of diseases, including cancer. Cellular and mitochondrial metabolism are both altered during the different stages of tumor development. As cancer cells have altered metabolic profiles, these alterations are a valid and promising target for anti-cancer agents. We hereby review several molecules that are in different stages of development and which target mitochondria in cancer cells. However, not all compounds are efficiently delivered into mitochondria, especially due to the difficulty of these agents to cross the membranes that surround the organelle, contributing to a loss of effectiveness and specificity. This led to the development of effective strategies aimed at delivering useful cargo to mitochondria, including the use of delocalized lipophilic cations coupled to useful molecules, or peptides that insert in mitochondrial membranes. Although several of those targeting strategies have still a very limited use against cancer cells, we present here the advantages and disadvantages of each combination.

Trends in Mitochondrial Therapeutics for Neurological Disease by Ana Leitão-Rocha, Pedro Guedes-Dias, Brígida R. Pinho, Jorge M. A. Oliveira (2458-2467).
Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These in clude not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindle-chromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondriatargeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models.

Regulation of Mitochondrial Function and its Impact in Metabolic Stress by Filipe V. Duarte, Joao A. Amorim, Carlos M. Palmeira, Anabela P. Rolo (2468-2479).
Mitochondria are key players in the maintenance of cellular homeostasis, as they generate ATP via OXPHOS. As such, disruption in mitochondrial homeostasis is closely associated with disease states, caused by subtle alterations in the function of tissues or by major defects, particularly evident in tissues with high metabolic demands. Adaptations in mitochondrial copy number or mitochondrial mass, and the induction of genes implicated in OXPHOS or in intermediary metabolism as well, depend on the balanced contribution of both the nuclear and mitochondrial genomes. This forms a biogenesis program, controlled by several nuclear factors that act coordinately and in a categorized manner. Dynamic changes in mitochondrial regulators are associated with post-translational modifications mediated by metabolic sensors, such as SIRT1 and AMPK. Nrf2, which induces an antioxidant protective response against oxidative stress, also modulates bioenergetic function and metabolism. Additionally, the stability of mitochondrial transcripts is decreased by miRNA detected in the mitochondria, thus affecting the bioenergetic capacity of the cell. However, mitochondrial adaptation to metabolic demands is also dependent on the removal of damaged mitochondria (mitophagy) and fission/fusion events of the mitochondrial network.

In the last twenty years, numerous reports provided solid evidence on the involvement of the mitochondrial permeability transition pore (PTP) in myocardial injury caused by ischemia and reperfusion. Indeed, significant cardioprotection is obtained by reducing the open probability of the PTP. This goal has been achieved by pharmacological and genetic interventions aimed at inhibiting cyclophilin D (CyPD), a regulatory protein that favors PTP opening. On the other hand, CyPD inhibition or deletion has been shown to worsen remodeling of the hypertrophic heart, an adverse outcome that must find an explanation within PTP modulation by CyPD. In this review, recent advancements in defining the molecular identity of the PTP are analyzed in relation to its pathophysiological functions and pharmacological modulation. In this respect, advantages and limitations of compounds targeting CyPD are discussed with the analysis of novel PTP inhibitors that do not interact with CyPD.

Mitochondrial toxicity is rapidly gaining the interest of researchers and practitioners as a prominent liability in drug discovery and development, accounting for a growing proportion of preclinical drug attrition and post-market withdrawals or black box warnings by the U.S. FDA. To date, the focus of registries of drugs that elicit mitochondrial toxicity has been largely restricted to those that either inhibit the mitochondrial electron transport chain (ETC) or uncouple mitochondrial oxidative phosphorylation. Less appreciated are the toxicities that are secondary to the drug affecting either the molecular regulation, assembly or incorporation of the ETC into the inner mitochondrial membrane or those that limit substrate availability. The current article describes the complexities of molecular events and biochemical pathways required to sustain mitochondrial fidelity and substrate homeostasis with examples of drugs that interfere which the various pathways. The principal objective of this review is to shed light on the broader scope of drug-induced mitochondrial toxicities and how these secondary targets may account for a large portion of drug failures.

Mitochondrial Mechanisms of Metabolic Reprogramming in Proliferating Cells by Maria Ines Sousa, Ana Sofia Rodrigues, Sandro Pereira, Tania Perestrelo, Marcelo Correia, Joao Ramalho-Santos (2493-2504).
Mitochondria are responsible for coordinating cellular energy production in the vast majority of somatic cells, and every cell type in a specific state can have a distinct metabolic signature. The metabolic requirements of cells from different tissues changes as they proliferate/differentiate, and cellular metabolism must match these demands. Proliferating cells, namely cancer cells and stem cells, tend to prefer glycolysis rather than a more oxidative metabolism. This preference has been exploited for the improvement of new biotechnological and therapeutic applications. In this review, we describe mitochondrial dynamics and energy metabolism modulation during nuclear reprogramming of somatic cells, which will be essential for the development and optimization of new protocols for regenerative medicine, disease modeling and toxicological screens involving patientspecific reprogrammed cells.