The Experts below are selected from a list of 97449 Experts worldwide ranked by ideXlab platform
Thomas Langer - One of the best experts on this subject based on the ideXlab platform.
-
m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration
Cell Research, 2018Co-Authors: Maria Patron, Hans-georg Sprenger, Thomas LangerAbstract:The function of mitochondria depends on ubiquitously expressed and evolutionary conserved m -AAA proteases in the inner membrane. These ATP-dependent peptidases form hexameric complexes built up of homologous subunits. AFG3L2 subunits assemble either into homo-oligomeric isoenzymes or with SPG7 (paraplegin) subunits into hetero-oligomeric proteolytic complexes. Mutations in AFG3L2 are associated with dominant spinocerebellar ataxia (SCA28) characterized by the loss of Purkinje cells, whereas mutations in SPG7 cause a recessive form of hereditary spastic paraplegia (HSP7) with motor neurons of the cortico-spinal tract being predominantly affected. Pleiotropic functions have been assigned to m -AAA proteases, which act as quality control and regulatory enzymes in mitochondria. Loss of m -AAA proteases affects mitochondrial protein synthesis and respiration and leads to mitochondrial fragmentation and deficiencies in the axonal transport of mitochondria. Moreover m -AAA proteases regulate the assembly of the m itochondrial c alcium u niporter (MCU) complex. Impaired degradation of the MCU subunit EMRE in AFG3L2-deficient mitochondria results in the formation of deregulated MCU complexes, increased mitochondrial calcium uptake and increased vulnerability of neurons for calcium-induced cell death. A reduction of calcium influx into the cytosol of Purkinje cells rescues ataxia in an AFG3L2-deficient mouse model. In this review, we discuss the relationship between the m -AAA protease and mitochondrial calcium homeostasis and its relevance for neurodegeneration and describe a novel mouse model lacking MCU specifically in Purkinje cells. Our results pledge for a novel view on m -AAA proteases that integrates their pleiotropic functions in mitochondria to explain the pathogenesis of associated neurodegenerative disorders.
-
mitochondrial AAA proteases towards a molecular understanding of membrane bound proteolytic machines
Biochimica et Biophysica Acta, 2012Co-Authors: Florian Gerdes, Thomas Langer, Takashi TatsutaAbstract:Mitochondrial AAA proteases play an important role in the maintenance of mitochondrial proteostasis. They regulate and promote biogenesis of mitochondrial proteins by acting as processing enzymes and ensuring the selective turnover of misfolded proteins. Impairment of AAA proteases causes pleiotropic defects in various organisms including neurodegeneration in humans. AAA proteases comprise ring-like hexameric complexes in the mitochondrial inner membrane and are functionally conserved from yeast to man, but variations are evident in the subunit composition of orthologous enzymes. Recent structural and biochemical studies revealed how AAA proteases degrade their substrates in an ATP dependent manner. Intersubunit coordination of the ATP hydrolysis leads to an ordered ATP hydrolysis within the AAA ring, which ensures efficient substrate dislocation from the membrane and translocation to the proteolytic chamber. In this review, we summarize recent findings on the molecular mechanisms underlying the versatile functions of mitochondrial AAA proteases and their relevance to those of the other AAA+ machines.
-
Autocatalytic Processing of m-AAA Protease Subunits in Mitochondria
Molecular biology of the cell, 2009Co-Authors: Mirko Koppen, Florian Bonn, Sarah Ehses, Thomas LangerAbstract:m-AAA proteases are ATP-dependent proteolytic machines in the inner membrane of mitochondria which are crucial for the maintenance of mitochondrial activities. Conserved nuclear-encoded subunits, termed paraplegin, Afg3l1, and Afg3l2, form various isoenzymes differing in their subunit composition in mammalian mitochondria. Mutations in different m-AAA protease subunits are associated with distinct neuronal disorders in human. However, the biogenesis of m-AAA protease complexes or of individual subunits is only poorly understood. Here, we have examined the processing of nuclear-encoded m-AAA protease subunits upon import into mitochondria and demonstrate autocatalytic processing of Afg3l1 and Afg3l2. The mitochondrial processing peptidase MPP generates an intermediate form of Afg3l2 that is matured autocatalytically. Afg3l1 or Afg3l2 are also required for maturation of newly imported paraplegin subunits after their cleavage by MPP. Our results establish that mammalian m-AAA proteases can act as processing enzymes in vivo and reveal overlapping activities of Afg3l1 and Afg3l2. These findings might be of relevance for the pathogenesis of neurodegenerative disorders associated with mutations in different m-AAA protease subunits.
-
Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease
Nature, 1999Co-Authors: Klaus Leonhard, Alexandra Stiegler, Walter Neupert, Thomas LangerAbstract:The AAA domain, a conserved Walker-type ATPase module, is a feature of members of the AAA family of proteins1,2, which are involved in many cellular processes, including vesicular transport3,4,5,6,7, organelle biogenesis8, microtubule rearrangement9 and protein degradation10,11,12. The function of the AAA domain, however, has not been explained. Membrane-anchored AAA proteases of prokaryotic and eukaryotic cells comprise a subfamily of AAA proteins13,14,15 that have metal-dependent peptidase activity and mediate the degradation of non-assembled membrane proteins. Inactivation of an orthologue of this protease family in humans causes neurodegeneration in hereditary spastic paraplegia16. Here we investigate the AAA domain of the yeast protein Yme1, a subunit of the i-AAA protease located in the inner membrane of mitochondria17,18. We show that Yme1 senses the folding state of solvent-exposed domains and specifically degrades unfolded membrane proteins. Substrate recognition and binding are mediated by the amino-terminal region of the AAA domain. The purified AAA domain of Yme1 binds unfolded polypeptides and suppresses their aggregation. Our results indicate that the AAA domain of Yme1 has a chaperone-like activity and suggest that the AAA domains of other AAA proteins may have a similar function.
Hyunseung Choo - One of the best experts on this subject based on the ideXlab platform.
-
ICCSA (2) - Route optimization with AAA in network mobility
Computational Science and Its Applications - ICCSA 2006, 2006Co-Authors: Kwangchul Jeong, Hyunseung ChooAbstract:In general, the nested mobile networks easily suffer from a bi-directional pinball routing with hierarchically multiple mobile routers. To handle this matter, several route optimization schemes have been proposed. But, to make network mobility feasible in public wireless Internet, well-defined authentication, authorization, and accounting protocols (AAA) should be accompanied. Hence, we combine a route optimization scheme with AAA architecture in network mobility in this paper. And we propose a new accounting system to support the combined architecture appropriately. We evaluate various existing route optimization schemes with AAA in terms of delay.
-
Route Optimization with AAA in Network Mobility
Lecture Notes in Computer Science, 2006Co-Authors: Kwangchul Jeong, Tae-jin Lee, Sungchang Lee, Hyunseung ChooAbstract:In general, the nested mobile networks easily suffer from a bi-directional pinball routing with hierarchically multiple mobile routers. To handle this matter, several route optimization schemes have been proposed. But, to make network mobility feasible in public wireless Internet, well-defined authentication, authorization, and accounting protocols (AAA) should be accompanied. Hence, we combine a route optimization scheme with AAA architecture in network mobility in this paper. And we propose a new accounting system to support the combined architecture appropriately. We evaluate various existing route optimization schemes with AAA in terms of delay.
Steven E. Glynn - One of the best experts on this subject based on the ideXlab platform.
-
AAA+ proteins: converging mechanisms, diverging functions
Nature Structural & Molecular Biology, 2020Co-Authors: Steven E. Glynn, Julia R. Kardon, Oliver Mueller-cajar, Carol ChoAbstract:The second Keystone Symposium on AAA+ proteins, “AAA+ Proteins: From Atomic Structures to Organisms”, was held in Tahoe City, USA in January 2020. The program highlighted recent advances from structural, biochemical and cellular approaches that have extended our understanding of these important ATP-driven molecular machines.
-
Multifunctional Mitochondrial AAA Proteases.
Frontiers in molecular biosciences, 2017Co-Authors: Steven E. GlynnAbstract:Mitochondria perform numerous functions necessary for the survival of eukaryotic cells. These activities are coordinated by a diverse complement of proteins encoded in both the nuclear and mitochondrial genomes that must be properly organized and maintained. Misregulation of mitochondrial proteostasis impairs organellar function and can result in the development of severe human diseases. ATP-driven AAA+ proteins play crucial roles in preserving mitochondrial activity by removing and remodeling protein molecules in accordance with the needs of the cell. Two mitochondrial AAA proteases, i-AAA and m-AAA, are anchored to either face of the mitochondrial inner membrane, where they engage and process an array of substrates to impact protein biogenesis, quality control, and the regulation of key metabolic pathways. The functionality of these proteases is extended through multiple substrate-dependent modes of action, including complete degradation, partial processing or dislocation from the membrane without proteolysis. This review discusses recent advances made towards elucidating the mechanisms of substrate recognition, handling, and degradation that allow these versatile proteases to control diverse activities in this multifunctional organelle.
Kwangchul Jeong - One of the best experts on this subject based on the ideXlab platform.
-
ICCSA (2) - Route optimization with AAA in network mobility
Computational Science and Its Applications - ICCSA 2006, 2006Co-Authors: Kwangchul Jeong, Hyunseung ChooAbstract:In general, the nested mobile networks easily suffer from a bi-directional pinball routing with hierarchically multiple mobile routers. To handle this matter, several route optimization schemes have been proposed. But, to make network mobility feasible in public wireless Internet, well-defined authentication, authorization, and accounting protocols (AAA) should be accompanied. Hence, we combine a route optimization scheme with AAA architecture in network mobility in this paper. And we propose a new accounting system to support the combined architecture appropriately. We evaluate various existing route optimization schemes with AAA in terms of delay.
-
Route Optimization with AAA in Network Mobility
Lecture Notes in Computer Science, 2006Co-Authors: Kwangchul Jeong, Tae-jin Lee, Sungchang Lee, Hyunseung ChooAbstract:In general, the nested mobile networks easily suffer from a bi-directional pinball routing with hierarchically multiple mobile routers. To handle this matter, several route optimization schemes have been proposed. But, to make network mobility feasible in public wireless Internet, well-defined authentication, authorization, and accounting protocols (AAA) should be accompanied. Hence, we combine a route optimization scheme with AAA architecture in network mobility in this paper. And we propose a new accounting system to support the combined architecture appropriately. We evaluate various existing route optimization schemes with AAA in terms of delay.
Geert Willem H. Schurink - One of the best experts on this subject based on the ideXlab platform.
-
The Influence of Wall Stress on AAA Growth and Biomarkers
ASME 2010 Summer Bioengineering Conference Parts A and B, 2010Co-Authors: Lambert Speelman, E. Marielle M. Bosboom, Michael J. Jacobs, Frans N. Van De Vosse, Femke A. M. V. I. Hellenthal, Marcel Breeuwer, Jaap Buth, Geert Willem H. SchurinkAbstract:In the decision for surgical repair of abdominal aortic aneurysms (AAAs), the risk of rupture is weighed carefully against the risk of the surgical procedure. The risk of rupture is estimated based on the maximum diameter and the growth rate of the AAA. Previous studies indicate that AAA growth rate increases with the diameter of the AAA [1, 2]. However, this growth rate is not the same for each AAA, as some AAA’s remain stable over a long period of time, while others show a fast growth or grow discontinuously.Copyright © 2010 by ASME
-
The influence of wall stress on AAA growth and biomarkers.
European Journal of Vascular and Endovascular Surgery, 2010Co-Authors: Lambert Speelman, E. Marielle M. Bosboom, Frans N. Van De Vosse, Femke A. M. V. I. Hellenthal, B. Pulinx, Marcel Breeuwer, M.r.h.m. Van Sambeek, Maria Jacobs, Will K. W. H. Wodzig, Geert Willem H. SchurinkAbstract:Abstract Objectives This study investigated the relation between abdominal aortic aneurysm (AAA) wall stress, AAA growth rate and biomarker concentrations. With increasing wall stress, more damage may be caused to the AAA wall, possibly leading to progression of the aneurysm and reflection in up- or downregulation of specific circulating biomarkers. Levels of matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1, C-reactive protein and alpha 1-antitrypsin were therefore evaluated. Methods Thirty-seven patients (maximum AAA diameter 41–55 mm) with two, three or four consecutive computed tomography angiography (CTA) scans were prospectively included. Diameter growth rate in mm/year was determined between each pair of two sequential CTA scans. AAA wall stress was computed by finite element analysis, based on the first of the two sequential CTA scans only ( n = 69 pairs). Biomarker information was determined in 46 measurements in 18 patients. The relation between AAA diameter and wall stress was determined and the AAA's were divided into three equally sized groups (relative low, medium and high stress). Growth rate and biomarker concentrations were compared between these groups. Additionally, correlation coefficients were computed between absolute wall stress, AAA growth and biomarker concentrations. Results A relative low AAA wall stress was associated with a lower aneurysm growth rate. Growth rate was also positively related to MMP-9 plasma concentration ( r = 0.32). The average MMP-9 and CRP concentrations increased with increasing degrees of relative wall stress, although the absolute and relative wall stress did not correlate with any of the biomarkers. Conclusion Although lower relative wall stress was associated to a lower AAA growth rate, no relation was found between biomarker concentrations and wall stress. Future research may focus on more and extensive biomarker measurements in relation to AAA wall stress.
-
AAA growth predicted with wall stress
2008Co-Authors: Lambert Speelman, E. Marielle M. Bosboom, Geert Willem H. Schurink, Mjhm Jacobs, Van De Fn Frans VosseAbstract:/department of biomedical engineering Introduction The risk of rupture of Abdominal Aortic Aneurysm (AAA) is nowadays estimated by the maximum AAA diameter and the diameter growth over time. We have shown previously that AAA wall stress, as computed with patient-specific finite element models, is strongly related to the AAA diameter [1]. Intraluminal thrombus (ILT) is found in most AAAs and may influence the computed wall stress.
-
Intraluminal Thrombus in AAA Wall Stress Analysis
ASME 2007 Summer Bioengineering Conference, 2007Co-Authors: Lambert Speelman, Evelyne A. Van Dam, G.w.m. Peters, E. Marielle M. Bosboom, Marcel C. M. Rutten, Geert Willem H. Schurink, Michael J. Jacobs, Frans N. Van De VosseAbstract:In previous research abdominal aortic aneurysm (AAA) wall stress analysis has proven to be more accurate in rupture risk prediction than the clinically used diameter criterion [1]. Together with Philips Medical Systems (Best, NL), a clinical software tool is created that automatically derives the AAA geometry from patient CT data and performs AAA wall stress analysis (Hemodyn package). Using this software package, the role of intraluminal thrombus (ILT) in AAA wall stress analysis is evaluated in this study.Copyright © 2007 by ASME
