56 results found
Sandrone S, Alavian KN, 2021, Threshold Concepts in Neuroscience: Identification Challenges, Educational Opportunities and Recommendations for Practice, FRONTIERS IN EDUCATION, Vol: 5
Niu Y, Moghimyfiroozabad S, Moghimyfiroozabad A, et al., 2021, The factors for the early and late development of midbrain dopaminergic neurons segregate into two distinct evolutionary clusters, Brain Disorders, Vol: 1, Pages: 1-8, ISSN: 2666-4593
Midbrain dopaminergic neurons are responsible for several functions in the reward system, control of emotion, motivation, cognition, and motor behavior. A set of well-characterized transcription factors involved in specification, neurogenesis, and neuronal differentiation determines the fate of these neurons and modulates their survival and maintenance postnatally. Identifying novel molecular connections with these factors might, therefore, lead to a better understanding of physiology as well as dysfunction and degeneration of these neurons in Parkinson's disease. To explore the links between developmental pathways and to identify novel linkages, we examined the correlations of phylogenetic profiles of these factors with those of the entire human proteome. Our analysis revealed two distinct evolutionary pathways comprising the early and late developmental factors and new linkages with these developmental cascades. These results suggest an evolutionary scenario for the development of the midbrain and dopaminergic neurons, with potential novel links to the canonical and non-canonical functions of the transcription factors.
Jonas E, Mnatsakanyan N, Alavian KN, et al., 2020, Mitochondrial (ATP Synthase) Permeability Transition Pore, 64th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 16A-16A, ISSN: 0006-3495
Fang Y, Liu C, Lin J, et al., 2019, PhySpeTree: an automated pipeline for reconstructing phylogenetic species trees, BMC Evolutionary Biology, Vol: 19, Pages: 1-8, ISSN: 1471-2148
BackgroundPhylogenetic species trees are widely used in inferring evolutionary relationships. Existing software and algorithms mainly focus on phylogenetic inference. However, less attention has been paid to intermediate steps, such as processing extremely large sequences and preparing configure files to connect multiple software. When the species number is large, the intermediate steps become a bottleneck that may seriously affect the efficiency of tree building.ResultsHere, we present an easy-to-use pipeline named PhySpeTree to facilitate the reconstruction of species trees across bacterial, archaeal, and eukaryotic organisms. Users need only to input the abbreviations of species names; PhySpeTree prepares complex configure files for different software, then automatically downloads genomic data, cleans sequences, and builds trees. PhySpeTree allows users to perform critical steps such as sequence alignment and tree construction by adjusting advanced options. PhySpeTree provides two parallel pipelines based on concatenated highly conserved proteins and small subunit ribosomal RNA sequences, respectively. Accessory modules, such as those for inserting new species, generating visualization configurations, and combining trees, are distributed along with PhySpeTree.ConclusionsTogether with accessory modules, PhySpeTree significantly simplifies tree reconstruction. PhySpeTree is implemented in Python running on modern operating systems (Linux, macOS, and Windows). The source code is freely available with detailed documentation (https://github.com/yangfangs/physpetools).
Weinert M, Cowley SA, Alavian KN, et al., 2019, Exploring the mitochondrial TSPO protein as a possible immunometabolic modulatory target for treatment of multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 515-515, ISSN: 1352-4585
Weinert M, Millet A, Jonas EA, et al., 2019, The mitochondrial metabolic function of DJ-1 is modulated by 14-3-3β., FASEB J, Vol: 33, Pages: 8925-8934
Mitochondrial metabolic plasticity is a key adaptive mechanism in response to changes in cellular metabolic demand. Changes in mitochondrial metabolic efficiency have been linked to pathophysiological conditions, including cancer, neurodegeneration, and obesity. The ubiquitously expressed DJ-1 (Parkinsonism-associated deglycase) is known as a Parkinson's disease gene and an oncogene. The pleiotropic functions of DJ-1 include reactive oxygen species scavenging, RNA binding, chaperone activity, endocytosis, and modulation of major signaling pathways involved in cell survival and metabolism. Nevertheless, how these functions are linked to the role of DJ-1 in mitochondrial plasticity is not fully understood. In this study, we describe an interaction between DJ-1 and 14-3-3β that regulates the localization of DJ-1, in a hypoxia-dependent manner, either to the cytosol or to mitochondria. This interaction acts as a modulator of mitochondrial metabolic efficiency and a switch between glycolysis and oxidative phosphorylation. Modulation of this novel molecular mechanism of mitochondrial metabolic efficiency is potentially involved in the neuroprotective function of DJ-1 as well as its role in proliferation of cancer cells.-Weinert, M., Millet, A., Jonas, E. A., Alavian, K. N. The mitochondrial metabolic function of DJ-1 is modulated by 14-3-3β.
Chen R, Park H-A, Mnatsakanyan N, et al., 2019, Parkinson's disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth, Cell Death and Disease, Vol: 10, ISSN: 2041-4889
Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 bindsdirectly to the F1FO ATP synthase β subunit. DJ-1’s interaction with the β subunit decreased mitochondrial uncouplingand enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrialuncoupling, and depolarized neuronal mitochondria. In mesencephalic DJ-1 KO cultures, there was a progressive lossof neuronal process extension. This was ameliorated by a pharmacological reagent, dexpramipexole, that binds to ATPsynthase, closing a mitochondrial inner membrane leak and enhancing ATP synthase efficiency. ATP synthase csubunit can form an uncoupling channel; we measured, therefore, ATP synthase F1 (β subunit) and c-subunit proteinlevels. We found that ATP synthase β subunit protein level in the DJ-1 KO neurons was approximately half that foundin their wild-type counterparts, comprising a severe defect in ATP synthase stoichiometry and unmasking c-subunit.We suggest that DJ-1 enhances dopaminergic cell metabolism and growth by its regulation of ATP synthase proteincomponents.
Mallach A, Weinert M, Arthur J, et al., 2019, Post mortem examination of Parkinson’s disease brains suggests decline in mitochondrial biomass, reversed by deep brain stimulation of subthalamic nucleus, The FASEB Journal, Pages: fj.201802628R-fj.201802628R, ISSN: 0892-6638
Niu Y, Moghimyfiroozabad S, Safaie S, et al., 2017, Phylogenetic Profiling of Mitochondrial Proteins and Integration Analysis of Bacterial Transcription Units Suggest Evolution of F1Fo ATP Synthase from Multiple Modules, Journal of Molecular Evolution, Vol: 85, Pages: 219-233, ISSN: 1432-1432
ATP synthase is a complex universal enzyme responsible for ATP synthesis across all kingdoms of life. The F-type ATPsynthase has been suggested to have evolved from two functionally independent, catalytic (F1) and membrane bound (Fo),ancestral modules. While the modular evolution of the synthase is supported by studies indicating independent assembly ofthe two subunits, the presence of intermediate assembly products suggests a more complex evolutionary process. We analyzedthe phylogenetic profiles of the human mitochondrial proteins and bacterial transcription units to gain additional insight intothe evolution of the F-type ATP synthase complex. In this study, we report the presence of intermediary modules based on thephylogenetic profiles of the human mitochondrial proteins. The two main intermediary modules comprise the α3β3 hexamerin the F1 and the c-subunit ring in the Fo. A comprehensive analysis of bacterial transcription units of F1Fo ATP synthaserevealed that while a long and constant order of F1Fo ATP synthase genes exists in a majority of bacterial genomes, highlyconserved combinations of separate transcription units are present among certain bacterial classes and phyla. Based on ourfindings, we propose a model that includes the involvement of multiple modules in the evolution of F1Fo ATP synthase. Thecentral and peripheral stalk subunits provide a link for the integration of the F1/Fo modules.
Niu Y, Liu C, Moghimyfiroozabad S, et al., 2017, PrePhyloPro: phylogenetic profile-based prediction of whole proteome linkages., PeerJ, Vol: 5, ISSN: 2167-8359
Direct and indirect functional links between proteins as well as their interactions as part of larger protein complexes or common signaling pathways may be predicted by analyzing the correlation of their evolutionary patterns. Based on phylogenetic profiling, here we present a highly scalable and time-efficient computational framework for predicting linkages within the whole human proteome. We have validated this method through analysis of 3,697 human pathways and molecular complexes and a comparison of our results with the prediction outcomes of previously published co-occurrency model-based and normalization methods. Here we also introduce PrePhyloPro, a web-based software that uses our method for accurately predicting proteome-wide linkages. We present data on interactions of human mitochondrial proteins, verifying the performance of this software. PrePhyloPro is freely available at http://prephylopro.org/phyloprofile/.
Park H-A, Licznerski P, Mnatsakanyan N, et al., 2017, Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity., Cell Death and Differentiation, Vol: 24, Pages: 1963-1974, ISSN: 1350-9047
ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ΔN-Bcl-xL. We now report that a high concentration of ABT-737 (1 μM), or a more selective Bcl-xL inhibitor WEHI-539 (5 μM) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10 nM) or WEHI-539 (10 nM) is neuroprotective. High ABT-737 markedly increased ΔN-Bcl-xL formation, aggravated glutamate-induced death and resulted in the loss of mitochondrial membrane potential and decline in ATP production. Although the usual cause of death by ABT-737 is thought to be related to activation of Bax at the outer mitochondrial membrane due to sequestration of Bcl-xL, we now find that low ABT-737 not only prevents Bax activation, but it also inhibits the decline in mitochondrial potential produced by glutamate toxicity or by direct application of ΔN-Bcl-xL to mitochondria. Loss of mitochondrial inner membrane potential is also prevented by cyclosporine A, implicating the mitochondrial permeability transition pore in death aggravated by ΔN-Bcl-xL. In keeping with this, we find that glutamate/ΔN-Bcl-xL-induced neuronal death is attenuated by depletion of the ATP synthase c-subunit. C-subunit depletion prevented depolarization of mitochondrial membranes in ΔN-Bcl-xL expressing cells and substantially prevented the morphological change in neurites associated with glutamate/ΔN-Bcl-xL insult. Our findings suggest that low ABT-737 or WEHI-539 promotes survival during glutamate toxicity by preventing the effect of ΔN-Bcl-xL on mit
Jonas EA, Mnatsakanyan N, Miranda P, et al., 2017, Mitochondria and Memory: Bioenergetics, Synaptic Plasticity and Neurodegeneration, 61st Annual Meeting of the Biophysical-Society, Publisher: Biophysical Society, Pages: 180A-180A, ISSN: 0006-3495
Jonas EA, Porter GA, Beutner G, et al., 2017, The Mitochondrial permeability transition pore: molecular structure and function in health and disease, Molecular Basis for Mitochondrial Signaling, Editors: Rostovtseva, Publisher: Springer International Publishing, Pages: 69-105, ISBN: 9783319555379
Ion transport across the mitochondrial inner and outer membranes is central to mitochondrial function, including regulation of oxidative phosphorylation and cell death. Although required for ATP production by mitochondria, recent findings have confirmed that the c-subunit of the ATP synthase also houses a large conductance uncoupling channel, the mitochondrial permeability transition pore (mPTP), the persistent opening of which produces osmotic dysregulation of the inner mitochondrial membrane and cell death. This chapter will discuss recent advances in understanding the molecular components of mPTP, its regulatory mechanisms during cell death, and its function in diseases of the brain. In contrast to mitochondrial inner membrane uncoupling, enhanced coupling occurs in states of improved mitochondrial efficiency; relative closure of mPTP therefore contributes to cell functions as diverse as cardiac development and synaptic efficacy.
Beutner G, Alavian KN, Jonas EA, et al., 2017, The Mitochondrial Permeability Transition Pore and ATP Synthase., Pages: 21-46
Mitochondrial ATP generation by oxidative phosphorylation combines the stepwise oxidation by the electron transport chain (ETC) of the reducing equivalents NADH and FADH2 with the generation of ATP by the ATP synthase. Recent studies show that the ATP synthase is not only essential for the generation of ATP but may also contribute to the formation of the mitochondrial permeability transition pore (PTP). We present a model, in which the PTP is located within the c-subunit ring in the Fo subunit of the ATP synthase. Opening of the PTP was long associated with uncoupling of the ETC and the initiation of programmed cell death. More recently, it was shown that PTP opening may serve a physiologic role: it can transiently open to regulate mitochondrial signaling in mature cells, and it is open in the embryonic mouse heart. This review will discuss how the ATP synthase paradoxically lies at the center of both ATP generation and cell death.
Beutner G, Alavian KN, Jonas EA, et al., 2017, Erratum to: The Mitochondrial Permeability Transition Pore and ATP Synthase.
Jonas EA, Miranda P, Gribkoff V, et al., 2016, PTP and LTP: The physiological role of the permeability transition pore in learning and memory, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol: 1857, Pages: e66-e67, ISSN: 0005-2728
Park H-A, Licznerski P, Niu Y, et al., 2016, Metabolic Control of Cell Death : The Role of Bcl-xL, Experimental Biology Meeting, Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638
Mnatsakanyan N, Beutner G, Porter GA, et al., 2016, Physiological roles of the mitochondrial permeability transition pore, JOURNAL OF BIOENERGETICS AND BIOMEMBRANES, Vol: 49, Pages: 13-25, ISSN: 0145-479X
Licznerski P, Duric V, Banasr M, et al., 2015, Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress, PLOS Biology, Vol: 13, ISSN: 1545-7885
Exposure to extreme stress can trigger the development of major depressive disorder(MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlyingthe structural and functional alterations within corticolimbic brain regions, including theprefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remainunknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1)expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, wedemonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- andanhedonic-like behaviors in rodent models. These behavioral changes are accompanied byabnormal dendritic spine morphology and synaptic dysfunction. Together, the results areconsistent with the possibility that altered SGK1 signaling contributes to the behavioral andmorphological phenotypes associated with traumatic stress pathophysiology.
Jonas EA, Porter GA, Beutner G, et al., 2015, The Mitochondrial Permeability Transition Pore, the c-Subunit of the F<inf>1</inf>F<inf>o</inf> ATP Synthase, Cellular Development, and Synaptic Efficiency, The Functions, Disease-Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria, Pages: 31-64, ISBN: 9781118709238
Ion transport across the mitochondrial inner and outer membranes is central to mitochondrial function, including regulation of oxidative phosphorylation and cell death. Although required for adenosine triphosphate (ATP) production by mitochondria, recent findings have confirmed that the c-subunit of the ATP synthase also houses a large conductance uncoupling channel, the mitochondrial permeability transition pore (mPTP), the persistent opening of which produces osmotic dysregulation of the inner mitochondrial membrane and cell death. This chapter discusses recent advances in understanding the molecular components of mPTP and its regulatory mechanisms during cell death. It also talks about mitochondrial inner and outer membrane channel activity, pathological outer mitochondrial membrane permeabilization (MOMP), mitochondrial permeability transition, the PT pore, and mitochondrial metabolic plasticity, among other concepts. Synaptic depression is also found acutely in hypoxic brain damage and may also be associated with opening of the c-subunit pore in its role as mPTP.
Jonas EA, Porter GA, Beutner G, et al., 2015, Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase, Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Zhao L, 2015, Iron homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular remodelling in the rat, Circulation Research, Vol: 116, Pages: 1680-1690, ISSN: 1524-4571
Rationale: Iron deficiency without anemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival.Objectives: We hypothesized that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy.Methods and Results: Rats were fed an iron-deficient diet (IDD, 7 mg/kg) and investigated for 4 weeks. Iron deficiency was evident from depleted iron stores (decreased liver, serum iron, and ferritin), reduced erythropoiesis, and significantly decreased transferrin saturation and lung iron stores after 2 weeks IDD. IDD rats exhibited profound pulmonary vascular remodeling with prominent muscularization, medial hypertrophy, and perivascular inflammatory cell infiltration, associated with raised pulmonary artery pressure and right ventricular hypertrophy. IDD rat lungs demonstrated increased expression of hypoxia-induced factor-1α and hypoxia-induced factor-2α, nuclear factor of activated T cells and survivin, and signal transducers and activators of transcription-3 activation, which promote vascular cell proliferation and resistance to apoptosis. Biochemical examination showed reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarization in mitochondria from IDD rat pulmonary arteries. Along with upregulation of the glucose transporter, glucose transporter 1, and glycolytic genes, hk1 and pdk1, lung fluorine-18–labeled 2-fluoro-2-deoxyglucose ligand uptake was significantly increased in IDD rats. The hemodynamic and pulmonary vascular remodeling were reversed by iron replacement (ferric carboxymaltose, 75 mg/kg) and attenuated in the presence of iron deficiency by dichloroacetate and imatinib, 2 putative treatments explored for pulmonary arterial hypertension that target aerobic glycolysis and proliferation, respectively.Conclusions: These data suggest a major role for iron in pulmonary vascular
Selvakumar T, Alavian KN, Tierney T, 2015, Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
Weinert M, Selvakumar T, Tierney TS, et al., 2015, Isolation, Culture and Long-Term Maintenance of Primary Mesencephalic Dopaminergic Neurons From Embryonic Rodent Brains, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
Park H-A, Licznerski P, Alavian KN, et al., 2015, Bcl-xL Is Necessary for Neurite Outgrowth in Hippocampal Neurons, ANTIOXIDANTS & REDOX SIGNALING, Vol: 22, Pages: 93-108, ISSN: 1523-0864
Alavian KN, Dworetzky SI, Bonanni L, et al., 2015, The Mitochondrial Complex V-Associated Large-Conductance Inner Membrane Current Is Regulated by Cyclosporine and Dexpramipexole, MOLECULAR PHARMACOLOGY, Vol: 87, Pages: 1-8, ISSN: 0026-895X
Jonas EA, Porter GA, Alavian KN, 2014, BcI-xL in neuroprotection and plasticity, FRONTIERS IN PHYSIOLOGY, Vol: 5, ISSN: 1664-042X
Alavian KN, Beutner G, Lazrove E, et al., 2014, An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore, Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 10580-10585, ISSN: 0027-8424
Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca2+) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity of the mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the FO of the F1FO ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca2+ enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F1, providing a mechanism for mPTP opening. In contrast, recombinant F1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca2+-induced IMM depolarization and inhibits Ca2+ and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.
Alavian KN, Jeddi S, Naghipour SI, et al., 2014, The lifelong maintenance of mesencephalic dopaminergic neurons by Nurr1 and engrailed, JOURNAL OF BIOMEDICAL SCIENCE, Vol: 21, ISSN: 1021-7770
Jonas E, Sacchetti S, Park H-A, et al., 2014, The C-Subunit of the ATP Synthase Forms the Pore of the PTP, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 3A-4A, ISSN: 0006-3495
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