Open Access
Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)
(Elsevier, 2016) Noskov, Sergei Y.; Rostovtseva, Tatiana K.; Chamberlin, Adam; Teijido Hermida, Óscar; Jiang, Wei; Bezrukov, Sergey M.; Ciencias de la Salud; Osasun Zientziak
Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane provides a controlled pathway for respiratory metabolites in and out of the mitochondria. In spite of the wealth of experimental data from structural, biochemical, and biophysical investigations, the exact mechanisms governing selective ion and metabolite transport, especially the role of titratable charged residues and interactions with soluble cytosolic proteins, remain hotly debated in the field. The computational advances hold a promise to provide a much sought-after solution to many of the scientific disputes around solute and ion transport through VDAC and hence, across the mitochondrial outer membrane. In this review, we examine how Molecular Dynamics, Free Energy, and Brownian Dynamics simulations of the large β-barrel channel, VDAC, advanced our understanding. We will provide a short overview of non-conventional techniques and also discuss examples of how the modeling excursions into VDAC biophysics prospectively aid experimental efforts.
Open Access
Population-based study of risk polymorphisms associated with vascular disorders and dementia
(Bentham Science Publishers, 2017) Teijido Hermida, Óscar; Carril, Juan Carlos ; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
Introduction: Cardiovascular and neurodegenerative disorders are among the major causes of mortality in the developed countries. Population studies evaluate the genetic risk, i.e. the probability of an individual carrying a specific disease-associated polymorphism. Identification of risk polymorphisms is essential for an accurate diagnosis or prognosis of a number of pathologies. Aims: The aim of this study was to characterize the influence of risk polymorphisms associated with lipid metabolism, hypertension, thrombosis, and dementia, in a large population of Spanish individuals affected by a variety of brain and vascular disorders as well as metabolic syndrome. Material & Method: We performed a cross-sectional study on 4415 individuals from a widespread regional distribution in Spain (48.15% males and 51.85% females), with mental, neurodegenerative, cerebrovascular, and metabolic disorders. We evaluated polymorphisms in 20 genes involved in obesity, vascular and cardiovascular risk, and dementia in our population and compared it with representative Spanish and European populations. Risk polymorphisms in ACE, AGT(235), IL6(573), PSEN1, and APOE (specially the APOE-ε4 allele) are representative of our population as compared to the reference data of Spanish and European individuals. Conclusion: The significantly higher distribution of risk polymorphisms in PSEN1 and APOE-ε4 is characteristic of a representative number of patients with Alzheimer’s disease; whereas polymorphisms in ACE, AGT(235), and IL6(573), are most probably related with the high number of patients with metabolic syndrome or cerebrovascular damage.
Open Access
MAC and Bcl-2 family proteins conspire in a deadly plot
(Elsevier, 2010-01-18) Dejean, Laurent M.; Ryu, Shin-Young; Martínez-Caballero, Sonia; Teijido Hermida, Óscar; Peixoto, Pablo M.; Kinnally, Kathleen W.; Ciencias de la Salud; Osasun Zientziak
Apoptosis is an elemental form of programmed cell death; it is fundamental to higher eukaryotes and essential to mechanisms controlling tissue homeostasis. Apoptosis is also involved in many pathologies including cancer, neurodegenerative diseases, aging, and infarcts. This cell death program is tightly regulated by Bcl-2 family proteins by controlling the formation of the mitochondrial apoptosis-induced channel or MAC. Assembly of MAC corresponds to permeabilization of the mitochondrial outer membrane, which is the so called commitment step of apoptosis. MAC provides the pathway through the mitochondrial outer membrane for the release of cytochrome c and other pro-apoptotic factors from the intermembrane space. While overexpression of anti-apoptotic Bcl-2 eliminates MAC activity, oligomers of the pro-apoptotic members Bax and/or Bak are essential structural component(s) of MAC. Assembly of MAC from Bax or Bak was monitored in real time by directly patch-clamping mitochondria with micropipettes containing the sentinel tBid, a direct activator of Bax and Bak. Herein, a variety of high affinity inhibitors of MAC (iMAC) that may prove to be crucial tools in mechanistic studies have recently been identified. This review focuses on characterization of MAC activity, its regulation by Bcl-2 family proteins, and a discussion of how MAC can be pharmacologically turned on or off depending on the pathology to be treated.
Open Access
Epigenetic mechanisms in the regulation of drug metabolism and transport
(Academic Press, 2019) Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Open Access
Pharmacoepigenomic interventions as novel potential treatments for Alzheimer's and Parkinson's diseases
(MDPI, 2018) Teijido Hermida, Óscar; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations.
Open Access
Can cloud-based tools accelerate Alzheimer's disease drug discovery?
(Taylor & Francis, 2016) Cacabelos, Ramón; Teijido Hermida, Óscar; Carril, Juan Carlos; Ciencias de la Salud; Osasun Zientziak
Open Access
Epigenetic drug discovery for alzheimer's disease
(Academic Press, 2018) Cacabelos, Ramón; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease (AD) is the most important neurodegenerative disorder in Western countries. Pathological phenotypes of neurodegeneration result from a combination of genomic, epigenomic, metabolic, and environmental factors, which hinders their treatment. Current FDA-approved conventional drugs are purely symptomatic but incapable to halt or, at least, delay the progression of the disease. The epigenetic approach allows the identification of key pathological targets in complex disorders that cannot be explained by conventional genetics. Many of these epigenetic targets may be detected in early asymptomatic stages of the disease. Furthermore, the reversibility and potential restoring of epigenetic aberrations, unlike genetic mutations, sited epigenetic-based therapy as a promising tool to treat those complex disorders. This chapter reviews the main potential epigenetic-based compounds that have been used for preclinical studies during the last decade and those currently submitted to clinical trials for the treatment of AD.
Open Access
Lipid dynamics and protein-lipid interactions in 2D crystals formed with the beta-barrel integral membrane protein VDAC1
(American Chemical Society, 2012) Eddy, Matthew T.; Ong, Ta-Chung; Clark, Lindsay; Teijido Hermida, Óscar; Van der Wel, Patrick C. A.; Garces, Robert; Wagner, Gerhard; Rostovtseva, Tatiana K.; Griffin, Robert G.; Ciencias de la Salud; Osasun Zientziak
We employ a combination of 13C/15N magic angle spinning (MAS) NMR and 2H NMR to study the structural and functional consequences of different membrane environments on VDAC1 and, conversely, the effect of VDAC1 on the structure of the lipid bilayer. MAS spectra reveal a well-structured VDAC1 in 2D crystals of dimyristoylphosphatidylcholine (DMPC) and diphytanoylphosphatidylcholine (DPhPC), and their temperature dependence suggests that the VDAC structure does not change conformation above and below the lipid phase transition temperature. The same data show that the N-terminus remains structured at both low and high temperatures. Importantly, functional studies based on electrophysiological measurements on these same samples show fully functional channels, even without the presence of Triton X-100 that has been found necessary for in vitro-refolded channels. 2H solid-state NMR and differential scanning calorimetry were used to investigate the dynamics and phase behavior of the lipids within the VDAC1 2D crystals. 2H NMR spectra indicate that the presence of protein in DMPC results in a broad lipid phase transition that is shifted from 19 to -27 °C and show the existence of different lipid populations, consistent with the presence of both annular and bulk lipids in the functionally and structurally homogeneous samples.
Open Access
Epigenetics of brain aging
(Academic Press, 2018) Cacabelos, Ramón; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
The complexity of human aging and longevity results from a combination of genetic, epigenetic, and environmental factors. Epigenetic mechanisms, including DNA methylation, chromatin structure, and RNA interference, regulate gene expression and control the main metabolic pathways throughout life. This strict epigenetic management becomes progressively defective with age, which increases the risk for the onset of age-related pathologies. This chapter reviews the main alterations of the epigenetic machinery throughout life, with special focus on those affecting the aging brain, as well as the epigenetic control of life span by regulating telomere length and mitochondrial function, with special emphasis on the epigenetic interplay between nuclear and mitochondrial DNA. The last section summarizes the main epigenetic aberrations involving the most prevalent form of pathologic brain deterioration in elderly individuals, Alzheimer's disease, and novel potential epigenetic-based treatments.
Open Access
The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation and conformation in yeast
(Elsevier, 2012) Renault, Thibaud T.; Grandier-Vazeille, Xavier; Arokium, Hubert; Velours, Gisèle; Camougrand, Nadine; Priault, Muriel; Teijido Hermida, Óscar; Dejean, Laurent M.; Manon, Stéphen; Ciencias de la Salud; Osasun Zientziak
The role of the mitochondrial protein receptor Tom22p in the interaction of pro-apoptotic protein Bax with yeast mitochondria was investigated. Co-immunoprecipitation assays showed that human Bax interacted with different TOM subunits, including Tom22p. Expression of the cytosolic receptor domain of human Tom22 increased Bax mitochondrial localization, but decreased the proportion of active Bax. BN-PAGE showed that the cytosolic domain of Tom22 interfered with the oligomerization of Bax. These data suggest that the interaction with the cytosolic domain of Tom22 helps Bax to acquire a conformation able to interact with the outer mitochondrial membrane.