60 results found
MacColl Garfinkel A, Mnatsakanyan N, Patel JH, et al., 2023, Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus, Developmental Cell, ISSN: 1534-5807
An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the “free” c-subunit ring of the F1Fo ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when β-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.
Sharifi P, Bae H, Gveric D, et al., 2022, CAV2.3 expression is upregulated in the substantia nigra pars compacta of humans with Parkinson's disease, Brain Disorders, Vol: 5, Pages: 1-3, ISSN: 2666-4593
Tierney TS, Alavian KN, Altman N, et al., 2021, Initial experience with magnetic resonance-guided focused ultrasound stereotactic surgery for central brain lesions in young adults, Journal of Neurosurgery, Vol: 137, Pages: 760-767, ISSN: 0022-3085
OBJECTIVEMagnetic resonance–guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population remains unknown.METHODSThe long-term outcomes of a prospective single-center, single-arm trial of MRgFUS at Nicklaus Children’s Hospital in Miami, Florida, are presented. Patients 15–22 years of age with centrally located lesions were recruited, clinically consistent with WHO grade I tumors that require surgical intervention. This cohort consisted of 4 patients with hypothalamic hamartoma (HH), and 1 patient with tuberous sclerosis complex harboring a subependymal giant cell astrocytoma (SEGA).RESULTSIn each case, high-intensity FUS was used to target the intracranial lesion. Real-time MRI was used to monitor the thermoablations. Primary outcomes of interest were tolerability, feasibility, and safety of FUS. The radiographic ablation volume on intra- and postoperative MRI was also assessed. All 5 patients tolerated the procedure without any complications. Successful thermoablation was achieved in 4 of the 5 cases; the calcified SEGA was undertreated due to intratumor calcification, which prevented attainment of the target ablation temperature. The HHs underwent target tissue thermoablations that led to MR signal changes at the treatment site. For the patients harboring HHs, FUS thermoablations occurred without procedure-related complications and led to improvement in seizure control or hypothalamic hyperphagia. All 5 patients were discharged home on postoperative day 1 or 2, without any readmissions. There were no cases of hemorrhage, electrolyte derangement, endocrinopathy, or new neurological deficit in this cohort.CONCLUSIONSThis experience demonstrates that FUS thermoablation of centrally located brain les
Sandrone S, Alavian KN, 2021, Threshold concepts in neuroscience: identification challenges, educational opportunities and recommendations for practice, Frontiers in Education, Vol: 5, Pages: 1-7, ISSN: 2504-284X
Threshold concepts are recent, yet already established, aspects of medical education. However, they represent a new area in neuroscience education, especially given the recency of neuroscience as a field of research in its own right when compared to more established STEM disciplines. In this article, we reviewed the existing literature on threshold concepts in clinical/translational neuroscience education and argued the relevance and the importance of biomarker as a new threshold concept. Moreover, we included a set of recommendations for practice that has the potential to improve the students' experience by offering them an authentic journey and, ultimately, to build a community of practice with shared goals and an enhanced diversity, with beneficial effects at several societal levels.
Alavian KN, Yu J-T, 2021, Disorders of the brain, paradoxes of the enigma, Brain Disorders, Vol: 1, Pages: 100003-100003, ISSN: 2666-4593
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, The FASEB Journal, Vol: 33, Pages: 8925-8934, ISSN: 0892-6638
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
Beutner G, Alavian KN, Jonas EA, et al., 2017, The Mitochondrial Permeability Transition Pore and ATP Synthase (vol 240, pg 21, 2016), PHARMACOLOGY OF MITOCHONDRIA, Editors: Singh, Sheu, Publisher: SPRINGER-VERLAG BERLIN, Pages: 489-489, ISBN: 978-3-319-57311-3
Beutner G, Alavian KN, Jonas EA, et al., 2017, The Mitochondrial Permeability Transition Pore and ATP Synthase, PHARMACOLOGY OF MITOCHONDRIA, Editors: Singh, Sheu, Publisher: SPRINGER-VERLAG BERLIN, Pages: 21-46, ISBN: 978-3-319-57311-3
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.
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
Jonas EA, Porter GA, Beutner G, et al., 2016, THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE, THE c-SUBUNIT OF THE F1Fo ATP SYNTHASE, CELLULAR DEVELOPMENT, AND SYNAPTIC EFFICIENCY, FUNCTIONS, DISEASE-RELATED DYSFUNCTIONS, AND THERAPEUTIC TARGETING OF NEURONAL MITOCHONDRIA, Editors: Gribkoff, Jonas, Hardwick, Publisher: JOHN WILEY & SONS INC, Pages: 31-64, ISBN: 978-1-118-70923-8
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, 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
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