Mitochondrial Medicine
2008; Lippincott Williams & Wilkins; Volume: 117; Issue: 19 Linguagem: Italiano
10.1161/circulationaha.108.775163
ISSN1524-4539
Autores Tópico(s)Metabolism and Genetic Disorders
ResumoHomeCirculationVol. 117, No. 19Mitochondrial Medicine Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMitochondrial MedicineA New Era in Medicine Opens New Windows and Brings New Challenges Evangelos D. Michelakis, MD Evangelos D. MichelakisEvangelos D. Michelakis From the Cardiology Division, Department of Medicine, University of Alberta, Edmonton, Canada. Originally published13 May 2008https://doi.org/10.1161/CIRCULATIONAHA.108.775163Circulation. 2008;117:2431–2434Socrates: … And he who is most skilled in preventing or escaping from a disease is best able to create one?Polemarchus: TrueSocrates: And is he the best guard of a camp who is best able to steal a march upon the enemy?Polemarchus: CertainlySocrates: Then he who is a good keeper of everything is also a good thief?Polemarchus: That I suppose is to be inferred— —Plato, The RepublicReading Plato one might not be surprised by the apparent paradox in the ability of mitochondria to promote both life and death: On the one hand, they are the major producers of energy in the cell, and on the other hand, they can steal the life of their host "at will." Mitochondria can sense the supply of fuel (they are important O2 sensors) and via the production of mediators (reactive O2 species [ROS]), communicate with critical effectors in the cell (like redox-sensitive ion channels in the membrane or the nucleus).1 In response to the needs of the cell, mitochondria produce both energy (ie, ATP) and heat, allowing the organism to work and keep a stable core temperature, facilitating optimal adaptation of eukaryotic cells to their environment. If the mitochondria cannot provide optimal adaptation to the metabolic needs and the environment, they have the ability to induce cell death (apoptosis). As strategic regulators of life and death, mitochondria are deeply involved in human disease, but the depth and breadth of mitochondria-based diseases is only now starting to be recognized.2Article p 2492Metabolism and apoptosis converge in mitochondria and are both recognized as playing a major role in disease. Primary metabolic abnormalities are now recognized in pulmonary and systemic vascular disease, and the apoptosis resistance seen in proliferative vascular remodeling might have a mitochondrial basis.3–5 Metabolic abnormalities are prominent in myocardial hypertrophy, and increased mitochondria-dependent apoptosis plays an important role in dilated cardiomyopathies.2 In cancer, the apoptosis resistance might have a mitochondrial basis,2,6 an idea first proposed by Warburg 80 years ago.7 In contrast, increased mitochondria-dependent apoptosis underlies the pathology of neurodegenerative diseases.2 Mitochondrial medicine is extending into common and serious diseases, beyond the narrow field of rare primary mitochondrial diseases. Mitochondrial genetics8 is leaving anthropology labs and is now used by epidemiology research teams.Mitochondrial Membrane Potential: A Master Regulator of Life and DeathMitochondria oxidize dietary hydrogen (carbohydrates and fats) with O2 to generate heat and ATP. Electrons donated from NADH and FADH2 (products of Krebs cycle) to complexes I and III of the electron transport chain (ETC), flow down a redox-gradient to complex IV and finally to O2 to give H2O (respiration). As electrons flow down the ETC, H+ from complexes I, III, and IV is pumped out of the mitochondrial matrix, creating a very negative potential, ΔΨm (>−240mV). In fact, mitochondria are the most negatively charged organelles in the cell. The stored energy in ΔΨm is used to synthesize ATP: As protons flow back into the matrix through a proton channel in complex V, ADP and Pi are bound, forming ATP (oxidative phosphorylation). Matrix ATP is then exchanged for cytosolic ADP.ATP Versus Heat Versus ROSThe efficiency by which dietary calories are converted to ATP versus heat is determined by the coupling efficiency between respiration and oxidative phosphorylation. If the ETC is efficient at pumping H+ out of the matrix (high ΔΨm) and the ATP synthesis is efficient at converting the H+ reentry into ATP, then the mitochondria will generate maximum ATP and minimum heat per calorie consumed (coupled mitochondria). If the efficiency of H+ pumping is reduced (low ΔΨm) then each calorie will produce less ATP and more heat (uncoupled mitochondria). Maintenance of a stable core temperature despite changing environmental conditions is critical, and in that sense ΔΨm, by determining the coupling efficiency, facilitates adjustment to the environment.8In coupled mitochondria, in the presence of excess calories and low cytoplasmic ADP (due to less exercise), complex V stops bringing H+ back in the matrix and thus ΔΨm increases; eventually the very negative potential prevents further H+ pumping and the ETC is stalled. As electrons keep coming in, they cannot be oxidized and interact with molecular O2, increasing ROS production. In contrast, decreased calories and high levels of ADP because of exercise result in H+ return into the matrix, decreasing the ΔΨm and ROS production. Could this explain the fact that low calorie intake and exercise have been associated with longevity and less cancer or cardiovascular disease (Figure, A)?2Download figureDownload PowerPointFigure. A, Top, The mitochondrial membrane potential (ΔΨm), directly affected by mtDNA mutations, is critical for many functions in health and disease, like ROS production, apoptosis, and production of energy versus heat. Bottom, ΔΨm can easily be measured by ΔΨm-dependent fluorescent dyes like TMRM. The apoptosis-resistant pulmonary artery vascular smooth muscle cells (VSMC) from patients with pulmonary hypertension and nonsmall lung cancer cells have higher ΔΨm (more red) compared with VSMC and lung epithelial cells from healthy subjects. B, Global mtDNA phylogeny: Neighbor joining of 1125 sequences is shown. Whereas the more central branches might have been driven by evolution, representing beneficial/adaptive mutations, the more recent ones in the periphery of the tree are more likely to be associated with human disease (see text). Reprinted from Wallace,8 with permission of the publisher. Copyright © 2007 Annual Reviews (www.annualreviews.org).In addition to diet and exercise, molecular mechanisms can directly alter the ΔΨm. Nuclear genes encode for uncoupling proteins (UCPs), channels that conduct H+, and, by being inserted into the mitochondria membranes, can "short circuit" the ΔΨm (ie, the H+ return back into the matrix without being linked to ATP production). This allows the nucleus to regulate mitochondria coupling by increasing the production of UCPs. Alternatively, the ΔΨm can be decreased by "defective" or "leaky" complexes I, III, IV, and V as a result of mutations in the genes encoding subunits of these megacomplexes. Therefore, UCP or a "leaky complex" can result in mitochondria producing more heat, allowing better adjustment to cold climates, and in that sense can be evolutionary beneficial.2,8 At the same time, many diseases result directly from such mutations or UCP abnormalities,2 including atherosclerosis.5Mitochondrial Transition PoreThe mitochondrial transition pore forms a megachannel that, when open, allows the efflux of proapoptotic mediators to the cytoplasm, activating protein breakdown (ie, apoptosis). The mitochondrial transition pore is both redox- and voltage-dependent, and decrease in ΔΨm promotes apoptosis.9 In contrast, mitochondrial hyperpolarization (increased ΔΨm) moves the mitochondrial transition pore away from the apoptotic threshold.Maximal hyperpolarization stalls respiration and oxidative phosphorylation, essentially "shutting off mitochondria" and shifting energy production to the cytoplasm, with glycolysis becoming the primary source of ATP. A glycolytic phenotype is associated with resistance to apoptosis, in part because the "inactive" hyperpolarized mitochondria cannot induce apoptosis.6 The majority of human cancers are characterized by hyperpolarized mitochondria, and this metabolic remodeling might be the basis of the Warburg effect in cancer.6,10 Intriguingly, the same mitochondrial hyperpolarization is also present in smooth muscle cells from human and animal pulmonary hypertension, explaining the apoptosis resistance that drives the proliferative vascular remodeling in this disease3,4 (Figure 1A). Thus, ΔΨm changes are seen in common diseases and can be induced by primary changes in ETC complexes, which could be a result of genetic changes. It is intriguing that the very few selected genes that form the mitochondrial DNA (mtDNA) are the ones encoding for ΔΨm-relevant complex subunits.2,8mtDNA: The Protected Holy Grail of a Relationship That Stood the Test of TimeA proto-mitochondrion/bacterion entered eukaryotic cells ≈2 to 3 billion years ago. As the symbiosis matured, many bacterial genes were transferred to the nucleus of the host cell, such that today the maternally inherited mtDNA retains only few genes. Intriguingly, these are the genes coding for critical subunits of the ETC complexes I-III-IV-V, all which are involved in H+ pumping (I-III-IV) or ATP/ADP transport and therefore regulate ΔΨm. In addition to those, mtDNA retained the genes for their transcription and translation (12S and 16S rRNAs and tRNAs), for a total of 37 genes. The remaining <1500 genes required for mitochondrial function are nucleus encoded, translated on cytosolic ribosomes, and imported into mitochondria through specialized import systems. These genes that are critical for ΔΨm never left the mitochondria despite the pressure for the nucleus to "take over."2,8 Thus, mtDNA can be seen as an index of ΔΨm, opening new windows into the many diseases caused by abnormal ATP production (ie, metabolism), apoptosis, or ROS-toxicity (Figure, A).Mitochondrial Genetics: Beyond MendelIn contrast to nDNA, mutations in mtDNA accumulate sequentially, in part because of the strict maternal inheritance and the high mutation rate in mtDNA.8 The history of human mtDNA mutations can be tracked back to their last common ancestor, 150 thousand to 200 thousand years ago, and can be reconstructed as a single sequential mutational tree (Figure, B).8 Intriguingly, tree branches were found to correlate significantly with region-specific mtDNA polymorphisms and the geographic origin of indigenous populations. These mtDNA variants are called haplotypes, and groups of related haplotypes forming a tree branch are called haplogroups. The 4 oldest haplogroups L0–1 to 2–3 are found in Africa. Haplogroups M and N branched out of L3 in northern Africa ≈65 thousand years ago. As Europe was populated ≈50 thousand years ago, many haplogroups arose from N, including H-(≈45% of European haplogroups)-T-U-V-W-X-I-J-Uk. In Asia, M and N branched out to A-B-F-C-d-G and others. Mixtures of B-A-C-D and X populations moved from Siberia and the Arctic Circle to the New World. Fascinating evidence now exists that the haplotypes found in populations residing in northern cold climates were promoting less-coupled mitochondrial function, generating more heat than ATP, thus facilitating adjustment to these environments.8Each cell hosts hundreds of mitochondria and copies of mtDNA. When an mtDNA mutation arises, a mixed population of mtDNAs is generated, a state known as heteroplasmy. At cell division, mutant and normal mtDNAs are randomly distributed into daughter cells, drifting toward homoplasmic mutant, wild-type, or intermediate states. Therefore, the cellular phenotype produced, in contrast to the binary Mendelian genetics, is the net sum of these mixed states.8 Deleterious mtDNA mutations resulting in abnormal mitochondria (less ATP, more ROS) can be amplified in a cell because the nucleus senses the lack of energy and commands the production of more (abnormal) mitochondria. Eventually, a critical threshold of ROS production is reached and apoptosis is induced, leading to disease. Because of genetic recombination, biparental inheritance of genes allows for species-wide spread of deleterious mutations that offer a replication advantage; perhaps in an effort to prevent this, the "fragile" mtDNA is now, after selection pressures, transmitted only maternally.8In this issue of Circulation, several European mtDNA haplogroups are shown to have no association with any cardiovascular or neoplastic disease or mortality.11 The Copenhagen City Heart Study provided blood and complete clinical data for 9254 patients, followed up for up to 25 years. In contrast to some associations with certain diseases shown by previous small case-control studies, the authors performed appropriate analysis, including multiple comparisons, that showed a lack of any associations. This is a well-done prospective study, and the authors need to be commended for their enormous effort, particularly in light of the negative results. Were the results expected? At first sight, given the importance of mitochondria in multiple aspects of health and disease, these results might appear surprising. However, a more careful approach suggests otherwise.The haplogroups studied by the authors are associated with critical points in migrations of humans and were likely driven by natural selection, allowing optimal adjustments to the environment. At large, these mutations were beneficial or adaptive. In that sense, they should not be expected to be markers of severe diseases. As can be seen in the tree in the Figure (B), several mutations have since been tracked beyond these early branching points, which suggests that the mutations are unlikely to be driven by environmental stimuli. Potentially deleterious mutations should be expected to be found later on in evolution, toward the periphery of the mutation tree. To detect disease associations with such mutations in large populations is not an easy task and requires creative polymerase chain reaction approaches to overcome the unique challenges of mitochondrial genetics, like heteroplasmy. Because of different mitotic rates and metabolic demands among different tissues, the degree of heteroplasmy varies among tissues, and that of circulating blood cells might be different from that of the myocardium in a patient with heart disease.In addition, the effort to identify a specific mutation as an independent risk factor for disease is based on the assumption that this is not related to other risk factors of the disease. This lack of relationship can be assumed in Mendelian genetics but is more challenging in mitochondrial genetics and in multifactorial diseases. For example, it is the accumulation of mtDNA mutations that increases with age that determines the disease phenotype, and therefore mitochondria-related diseases are often diseases of old age (cardiovascular or neurodegenerative diseases).2 Therefore, the ability of 1 mtDNA mutation to directly cause or facilitate a disease needs to be separated from simply its accumulation with age. Even then, the phenotype cannot be predicted by the presence of a mutation without knowing the degree of heteroplasmy. At this point, difficulties in the establishment of mtDNA mutations in animal models make genotype–phenotype associations in human diseases even more difficult.Studies like this should inspire us for the effort, with the meticulous approach followed by the investigators and their courage to report a negative finding, which often enjoys less enthusiastic response than "typical" positive studies. However, like all good science, the study offers more questions and challenges for the future than answers, a necessary process for the momentum that the new mitochondrial medicine needs.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Evangelos D. Michelakis, MD, Cardiology Division, Department of Medicine, University of Alberta, 2C2.36 Walter Mackenzie Health Sciences Centre, 8440 112th St, Alberta, Edmonton T6G 2B7, Canada. References 1 Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med. 2005; 353: 2042–2055.CrossrefMedlineGoogle Scholar2 Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39: 359–407.CrossrefMedlineGoogle Scholar3 McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest. 2005; 115: 1479–1491.CrossrefMedlineGoogle Scholar4 McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004; 95: 830–840.LinkGoogle Scholar5 Bernal-Mizrachi C, Gates AC, Weng S, Imamura T, Knutsen RH, DeSantis P, Coleman T, Townsend RR, Muglia LJ, Semenkovich CF. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature. 2005; 435: 502–506.CrossrefMedlineGoogle Scholar6 Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer, and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11: 37–51.CrossrefMedlineGoogle Scholar7 Warburg O. On Metabolism of Tumors. London, United Kingdom. Constable; 1930.Google Scholar8 Wallace DC. Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu Rev Biochem. 2007; 76: 781–821.CrossrefMedlineGoogle Scholar9 Zamzami N, Kroemer G. The mitochondrion in apoptosis: how Pandora's box opens. Nat Rev Mol Cell Biol. 2001; 2: 67–71.CrossrefMedlineGoogle Scholar10 Chen LB. Mitochondrial membrane potential in living cells. Annu Rev Cell Biol. 1988; 4: 155–181.CrossrefMedlineGoogle Scholar11 Benn M, Schwartz M, Nordestgaard BG, Tybjærg-Hansen A. Mitochondrial haplogroups: ischemic cardiovascular disease, other diseases, mortality, and longevity in the general population. Circulation. 2008; 117: 2492–2501.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Singh H (2021) Mitochondrial ion channels in cardiac function, American Journal of Physiology-Cell Physiology, 10.1152/ajpcell.00246.2021, 321:5, (C812-C825), Online publication date: 1-Nov-2021. Nakamura Y, Lo E and Hayakawa K (2020) Placental Mitochondria Therapy for Cerebral Ischemia-Reperfusion Injury in Mice, Stroke, 51:10, (3142-3146), Online publication date: 1-Oct-2020. Hall A, Maynard S, Wu L, Merchut-Maya J, Strauss R, Moghimi S and Bartek J (2019) Perturbation of mitochondrial bioenergetics by polycations counteracts resistance to BRAFE600 inhibition in melanoma cells, Journal of Controlled Release, 10.1016/j.jconrel.2019.07.032, 309, (158-172), Online publication date: 1-Sep-2019. Aw W, Garvin M and Ballard J (2019) Exogenous Factors May Differentially Influence the Selective Costs of mtDNA Mutations Cellular and Molecular Basis of Mitochondrial Inheritance, 10.1007/102_2018_2, (51-74), . Gollihue J and Rabchevsky A (2017) Prospects for therapeutic mitochondrial transplantation, Mitochondrion, 10.1016/j.mito.2017.05.007, 35, (70-79), Online publication date: 1-Jul-2017. Yang Y, Ren L and Wang H (2017) Strategies in the design of gold nanoparticles for intracellular targeting: opportunities and challenges, Therapeutic Delivery, 10.4155/tde-2017-0049, 8:10, (879-897), Online publication date: 1-Oct-2017. Chen Y, Shiau A, Chang S, Fan N, Wang C, Wu C and Jan J (2017) One-dimensional poly(L-lysine)-block-poly(L-threonine) assemblies exhibit potent anticancer activity by enhancing membranolysis, Acta Biomaterialia, 10.1016/j.actbio.2017.04.009, 55, (283-295), Online publication date: 1-Jun-2017. Ito S, Asakura M, Liao Y, Min K, Takahashi A, Shindo K, Yamazaki S, Tsukamoto O, Asanuma H, Mogi M, Horiuchi M, Asano Y, Sanada S, Minamino T, Takashima S, Mochizuki N and Kitakaze M (2016) Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy, Journal of the American Heart Association, 5:7, Online publication date: 6-Jul-2016. Kelly J and Murphy J (2016) Mitochondrial tolerance to single and repeat exposure to simulated sunlight in human epidermal and dermal skin cells, Journal of Photochemistry and Photobiology B: Biology, 10.1016/j.jphotobiol.2016.11.005, 165, (298-304), Online publication date: 1-Dec-2016. Wang S, Qiu J, Shi Z, Wang Y and Chen M (2015) Nanoscale drug delivery for taxanes based on the mechanism of multidrug resistance of cancer, Biotechnology Advances, 10.1016/j.biotechadv.2014.10.011, 33:1, (224-241), Online publication date: 1-Jan-2015. Yang Y, Gao N, Hu Y, Jia C, Chou T, Du H and Wang H (2015) Gold nanoparticle-enhanced photodynamic therapy: effects of surface charge and mitochondrial targeting, Therapeutic Delivery, 10.4155/tde.14.115, 6:3, (307-321), Online publication date: 1-Apr-2015. Johnson P, Vaduganathan M, Phillips K and O'Donnell W (2017) A Triad of Linezolid Toxicity: Hypoglycemia, Lactic Acidosis, and Acute Pancreatitis, Baylor University Medical Center Proceedings, 10.1080/08998280.2015.11929310, 28:4, (466-468), Online publication date: 1-Oct-2015. Gonzalez-Suarez I, Sewer A, Walker P, Mathis C, Ellis S, Woodhouse H, Guedj E, Dulize R, Marescotti D, Acali S, Martin F, Ivanov N, Hoeng J and Peitsch M (2014) Systems Biology Approach for Evaluating the Biological Impact of Environmental Toxicants in Vitro , Chemical Research in Toxicology, 10.1021/tx400405s, 27:3, (367-376), Online publication date: 17-Mar-2014. Popov A and Menchikov L (2013) The Warburg Effect Is a Guide to Multipurpose Cancer Therapy Including Trace Element Delivery Drug Delivery Systems: Advanced Technologies Potentially Applicable in Personalised Treatment, 10.1007/978-94-007-6010-3_9, (255-270), . Pokorný J, Foletti A, Kobilková J, Jandová A, Vrba J, Vrba J, Nedbalová M, Čoček A, Danani A and Tuszyński J (2013) Biophysical Insights into Cancer Transformation and Treatment, The Scientific World Journal, 10.1155/2013/195028, 2013, (1-11), . McMurtry M (2013) Angiogenesis, Arteriogenesis, and Mitochondrial Dysfunction Cardiac Remodeling, 10.1007/978-1-4614-5930-9_15, (255-272), . Aravamudan B, Thompson M, Pabelick C and Prakash Y (2014) Mitochondria in lung diseases, Expert Review of Respiratory Medicine, 10.1586/17476348.2013.834252, 7:6, (631-646), Online publication date: 1-Dec-2013. Rutledge C and Dudley S (2014) Mitochondria and arrhythmias, Expert Review of Cardiovascular Therapy, 10.1586/14779072.2013.811969, 11:7, (799-801), Online publication date: 1-Jul-2013. Gonzalez M, Miranda Massari J, Duconge J, Riordan N, Ichim T, Quintero-Del-Rio A and Ortiz N (2012) The bio-energetic theory of carcinogenesis, Medical Hypotheses, 10.1016/j.mehy.2012.06.015, 79:4, (433-439), Online publication date: 1-Oct-2012. Pokorný J, Jandová A, Nedbalová M, Jelínek F, Cifra M, Kučera O, Havelka D, Vrba J, Vrba J, Čoček A and Kobilková J (2015) Mitochondrial Metabolism – Neglected Link of Cancer Transformation and Treatment, Prague Medical Report, 10.14712/23362936.2015.24, 113:2, (81-94), . Akar F and O'Rourke B (2011) Mitochondria are sources of metabolic sink and arrhythmias, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2011.04.005, 131:3, (287-294), Online publication date: 1-Sep-2011. Bartelds B, Borgdorff M, Smit-van Oosten A, Takens J, Boersma B, Nederhoff M, Elzenga N, van Gilst W, De Windt L and Berger R (2014) Differential responses of the right ventricle to abnormal loading conditions in mice: pressure vs. volume load, European Journal of Heart Failure, 10.1093/eurjhf/hfr134, 13:12, (1275-1282), Online publication date: 1-Dec-2011. Haddad F, Skhiri M and Michelakis E (2011) Right Ventricular Dysfunction in Pulmonary Hypertension Textbook of Pulmonary Vascular Disease, 10.1007/978-0-387-87429-6_94, (1313-1331), . Haddad F, Ashley E and Michelakis E (2010) New insights for the diagnosis and management of right ventricular failure, from molecular imaging to targeted right ventricular therapy, Current Opinion in Cardiology, 10.1097/HCO.0b013e328335febd, 25:2, (131-140), Online publication date: 1-Mar-2010. Skhiri M, Hunt S, Denault A and Haddad F (2010) Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Field, Revista Española de Cardiología (English Edition), 10.1016/S1885-5857(10)70094-3, 63:4, (451-471), Online publication date: 1-Apr-2010. Skhiri M, Hunt S, Denault A and Haddad F (2010) Tratamiento basado en la evidencia de la insuficiencia cardiaca derecha: una revisión sistemática de un campo empírico, Revista Española de Cardiología, 10.1016/S0300-8932(10)70066-X, 63:4, (451-471), Online publication date: 1-Apr-2010. Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes K, Lopaschuk G, Dyck J and Michelakis E (2010) Fatty Acid Oxidation and Malonyl-CoA Decarboxylase in the Vascular Remodeling of Pulmonary Hypertension, Science Translational Medicine, 10.1126/scitranslmed.3001327, 2:44, Online publication date: 11-Aug-2010. Kallianpur A and Hulgan T (2009) Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy, Pharmacogenomics, 10.2217/pgs.09.14, 10:4, (623-637), Online publication date: 1-Apr-2009. Roth M and Black J (2009) An imbalance in C/EBPs and increased mitochondrial activity in asthmatic airway smooth muscle cells: novel targets in asthma therapy?, British Journal of Pharmacology, 10.1111/j.1476-5381.2009.00188.x, 157:3, (334-341) Käding N, Kaufhold I, Müller C, Szaszák M, Shima K, Weinmaier T, Lomas R, Conesa A, Schmitt-Kopplin P, Rattei T and Rupp J (2017) Growth of Chlamydia pneumoniae Is Enhanced in Cells with Impaired Mitochondrial Function, Frontiers in Cellular and Infection Microbiology, 10.3389/fcimb.2017.00499, 7 Pepin É, Al-Mass A, Attané C, Zhang K, Lamontagne J, Lussier R, Madiraju S, Joly E, Ruderman N, Sladek R, Prentki M, Peyot M and Nadal A (2016) Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression, PLOS ONE, 10.1371/journal.pone.0153017, 11:4, (e0153017) May 13, 2008Vol 117, Issue 19 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.108.775163PMID: 18474822 Originally publishedMay 13, 2008 KeywordsapoptosisEditorialscardiovascular diseasesatherosclerosisgeneticsmetabolismPDF download Advertisement SubjectsCell Signaling/Signal TransductionEpidemiologyGeneticsMetabolismOxidant StressPulmonary BiologyVascular Biology
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