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https://www.readbyqxmd.com/read/27786171/engineered-aaa-proteases-reveal-principles-of-proteolysis-at-the-mitochondrial-inner-membrane
#1
Hui Shi, Anthony J Rampello, Steven E Glynn
The human YME1L protease is a membrane-anchored AAA+ enzyme that controls proteostasis at the inner membrane and intermembrane space of mitochondria. Understanding how YME1L recognizes substrates and catalyses ATP-dependent degradation has been hampered by the presence of an insoluble transmembrane anchor that drives hexamerization of the catalytic domains to form the ATPase active sites. Here, we overcome this limitation by replacing the transmembrane domain with a soluble hexameric coiled coil to produce active YME1L hexamers that can be studied in vitro...
October 27, 2016: Nature Communications
https://www.readbyqxmd.com/read/27737933/the-membrane-scaffold-slp2-anchors-a-proteolytic-hub-in-mitochondria-containing-parl-and-the-i-aaa-protease-yme1l
#2
Timothy Wai, Shotaro Saita, Hendrik Nolte, Sebastian Müller, Tim König, Ricarda Richter-Dennerlein, Hans-Georg Sprenger, Joaquin Madrenas, Mareike Mühlmeister, Ulrich Brandt, Marcus Krüger, Thomas Langer
The SPFH (stomatin, prohibitin, flotillin, HflC/K) superfamily is composed of scaffold proteins that form ring-like structures and locally specify the protein-lipid composition in a variety of cellular membranes. Stomatin-like protein 2 (SLP2) is a member of this superfamily that localizes to the mitochondrial inner membrane (IM) where it acts as a membrane organizer. Here, we report that SLP2 anchors a large protease complex composed of the rhomboid protease PARL and the i-AAA protease YME1L, which we term the SPY complex (for SLP2-PARL-YME1L)...
December 2016: EMBO Reports
https://www.readbyqxmd.com/read/27189080/opa1-processing-in-cell-death-and-disease-the-long-and-short-of-it
#3
REVIEW
Thomas MacVicar, Thomas Langer
The regulation of mitochondrial dynamics by the GTPase OPA1, which is located at the inner mitochondrial membrane, is crucial for adapting mitochondrial function and preserving cellular health. OPA1 governs the delicate balance between fusion and fission in the dynamic mitochondrial network. A disturbance of this balance, often observed under stress and pathologic conditions, causes mitochondrial fragmentation and can ultimately result in cell death. As discussed in this Commentary, these morphological changes are regulated by proteolytic processing of OPA1 by the inner-membrane peptidases YME1L (also known as YME1L1) and OMA1...
June 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/26965961/-mitotherapy-for-heart-failure
#4
COMMENT
Fabian Sanchis-Gomar, Giuseppe Lippi, Alejandro Lucia
Abnormalities in mitochondrial dynamics along with those for the molecular mediators involved are presently being viewed with increased interest in the field of cardiovascular disease. Recent research highlights OPA1, a dynamin-like GTPase mediating mitochondrial fusion, as well as the 'mitoproteases' OMA1 and YME1L, as potential therapeutic targets against heart failure.
April 2016: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/26923599/reciprocal-degradation-of-yme1l-and-oma1-adapts-mitochondrial-proteolytic-activity-during-stress
#5
T Kelly Rainbolt, Justine Lebeau, Cristina Puchades, R Luke Wiseman
The mitochondrial inner membrane proteases YME1L and OMA1 are critical regulators of essential mitochondrial functions, including inner membrane proteostasis maintenance and mitochondrial dynamics. Here, we show that YME1L and OMA1 are reciprocally degraded in response to distinct types of cellular stress. OMA1 is degraded through a YME1L-dependent mechanism in response to toxic insults that depolarize the mitochondrial membrane. Alternatively, insults that depolarize mitochondria and deplete cellular ATP stabilize active OMA1 and promote YME1L degradation...
March 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/26785494/imbalanced-opa1-processing-and-mitochondrial-fragmentation-cause-heart-failure-in-mice
#6
Timothy Wai, Jaime García-Prieto, Michael J Baker, Carsten Merkwirth, Paule Benit, Pierre Rustin, Francisco Javier Rupérez, Coral Barbas, Borja Ibañez, Thomas Langer
Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure...
December 4, 2015: Science
https://www.readbyqxmd.com/read/26759378/the-mammalian-homologue-of-yeast-afg1-atpase-lactation-elevated-1-mediates-degradation-of-nuclear-encoded-complex-iv-subunits
#7
Jana Cesnekova, Marie Rodinova, Hana Hansikova, Josef Houstek, Jiri Zeman, Lukas Stiburek
Mitochondrial protein homeostasis is crucial for cellular function and integrity and is therefore maintained by several classes of proteins possessing chaperone and/or proteolytic activities. In the present study, we focused on characterization of LACE1 (lactation elevated 1) function in mitochondrial protein homeostasis. LACE1 is the human homologue of yeast mitochondrial Afg1 (ATPase family gene 1) ATPase, a member of the SEC18-NSF, PAS1, CDC48-VCP, TBP family. Yeast Afg1 was shown to mediate degradation of mitochondrially encoded complex IV subunits, and, on the basis of its similarity to CDC48 (p97/VCP), it was suggested to facilitate extraction of polytopic membrane proteins...
March 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/26393574/mitochondrial-optic-atrophy-opa-1-processing-is-altered-in-response-to-neonatal-hypoxic-ischemic-brain-injury
#8
Ana A Baburamani, Chloe Hurling, Helen Stolp, Kristina Sobotka, Pierre Gressens, Henrik Hagberg, Claire Thornton
Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment...
September 17, 2015: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/26250910/mic60-mitofilin-determines-micos-assembly-essential-for-mitochondrial-dynamics-and-mtdna-nucleoid-organization
#9
H Li, Y Ruan, K Zhang, F Jian, C Hu, L Miao, L Gong, L Sun, X Zhang, S Chen, H Chen, D Liu, Z Song
The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae...
March 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/25433032/yme1l-degradation-reduces-mitochondrial-proteolytic-capacity-during-oxidative-stress
#10
T Kelly Rainbolt, Jaclyn M Saunders, R Luke Wiseman
Mitochondrial proteostasis is maintained by a network of ATP-dependent quality control proteases including the inner membrane protease YME1L. Here, we show that YME1L is a stress-sensitive mitochondrial protease that is rapidly degraded in response to acute oxidative stress. This degradation requires reductions in cellular ATP and involves the activity of the ATP-independent protease OMA1. Oxidative stress-dependent reductions in YME1L inhibit protective YME1L-dependent functions and increase cellular sensitivity to oxidative insult...
January 2015: EMBO Reports
https://www.readbyqxmd.com/read/24719224/membrane-depolarization-activates-the-mitochondrial-protease-oma1-by-stimulating-self-cleavage
#11
Kuan Zhang, Huihui Li, Zhiyin Song
Mitochondrial inner membrane fusion depends on the dynamin-related GTPase OPA1 and the function of OPA1 is regulated by proteolytic cleavage. The mitochondrial proteases Yme1L and OMA1 cleave OPA1 at S2 and S1 sites, respectively. Here, we show that OMA1 is cleaved to a short form (S-OMA1) by itself upon mitochondrial membrane depolarization; S-OMA1 is degraded quickly but could be stabilized by CCCP treatment or Prohibitin knockdown in cells. In addition, OMA1 processing is positively correlated with OPA1 cleavage at the S1 site and the regulation of mitochondrial morphology...
May 2014: EMBO Reports
https://www.readbyqxmd.com/read/24703695/proteolytic-cleavage-of-opa1-stimulates-mitochondrial-inner-membrane-fusion-and-couples-fusion-to-oxidative-phosphorylation
#12
Prashant Mishra, Valerio Carelli, Giovanni Manfredi, David C Chan
Mitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion...
April 1, 2014: Cell Metabolism
https://www.readbyqxmd.com/read/24616225/the-i-aaa-protease-yme1l-and-oma1-cleave-opa1-to-balance-mitochondrial-fusion-and-fission
#13
Ruchika Anand, Timothy Wai, Michael J Baker, Nikolay Kladt, Astrid C Schauss, Elena Rugarli, Thomas Langer
Mitochondrial fusion and structure depend on the dynamin-like GTPase OPA1, whose activity is regulated by proteolytic processing. Constitutive OPA1 cleavage by YME1L and OMA1 at two distinct sites leads to the accumulation of both long and short forms of OPA1 and maintains mitochondrial fusion. Stress-induced OPA1 processing by OMA1 converts OPA1 completely into short isoforms, inhibits fusion, and triggers mitochondrial fragmentation. Here, we have analyzed the function of different OPA1 forms in cells lacking YME1L, OMA1, or both...
March 17, 2014: Journal of Cell Biology
https://www.readbyqxmd.com/read/24315374/stress-regulated-translational-attenuation-adapts-mitochondrial-protein-import-through-tim17a-degradation
#14
T Kelly Rainbolt, Neli Atanassova, Joseph C Genereux, R Luke Wiseman
Stress-regulated signaling pathways protect mitochondrial proteostasis and function from pathologic insults. Despite the importance of stress-regulated signaling pathways in mitochondrial proteome maintenance, the molecular mechanisms by which these pathways maintain mitochondrial proteostasis remain largely unknown. We identify Tim17A as a stress-regulated subunit of the translocase of the inner membrane 23 (TIM23) mitochondrial protein import complex. We show that Tim17A protein levels are decreased downstream of stress-regulated translational attenuation induced by eukaryotic initiation factor 2α (eIF2α) phosphorylation through a mechanism dependent on the mitochondrial protease YME1L...
December 3, 2013: Cell Metabolism
https://www.readbyqxmd.com/read/24176854/loss-of-yme1l-perturbates-mitochondrial-dynamics
#15
Y Ruan, H Li, K Zhang, F Jian, J Tang, Z Song
Yme1L is an AAA protease that is embedded in the mitochondrial inner membrane with its catalytic domain facing the mitochondrial inner-membrane space. However, how Yme1L regulates mammalian mitochondrial function is still obscure. We find that endogenous Yme1L locates at punctate structures of mitochondria, and that loss of Yme1L in mouse embryonic fibroblast (MEF) cells results in mitochondrial fragmentation and leads to significant increased 'kiss-and-run' type of mitochondrial fusion; however, Yme1L knockdown (shYme1L (short hairpin-mediated RNA interference of Yme1L)) cells still remain normal mitochondrial fusion although shYme1L mitochondria have a little bit less fusion and fission rates, and the shYme1L-induced fragmentation is due to a little bit more mitochondrial fission than fusion in cells...
2013: Cell Death & Disease
https://www.readbyqxmd.com/read/22262461/yme1l-controls-the-accumulation-of-respiratory-chain-subunits-and-is-required-for-apoptotic-resistance-cristae-morphogenesis-and-cell-proliferation
#16
Lukas Stiburek, Jana Cesnekova, Olga Kostkova, Daniela Fornuskova, Kamila Vinsova, Laszlo Wenchich, Josef Houstek, Jiri Zeman
Mitochondrial ATPases associated with diverse cellular activities (AAA) proteases are involved in the quality control and processing of inner-membrane proteins. Here we investigate the cellular activities of YME1L, the human orthologue of the Yme1 subunit of the yeast i-AAA complex, using stable short hairpin RNA knockdown and expression experiments. Human YME1L is shown to be an integral membrane protein that exposes its carboxy-terminus to the intermembrane space and exists in several complexes of 600-1100 kDa...
March 2012: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/20038677/inducible-proteolytic-inactivation-of-opa1-mediated-by-the-oma1-protease-in-mammalian-cells
#17
Brian Head, Lorena Griparic, Mandana Amiri, Shilpa Gandre-Babbe, Alexander M van der Bliek
The mammalian mitochondrial inner membrane fusion protein OPA1 is controlled by complex patterns of alternative splicing and proteolysis. A subset of OPA1 isoforms is constitutively cleaved by YME1L. Other isoforms are not cleaved by YME1L, but they are cleaved when mitochondria lose membrane potential or adenosine triphosphate. In this study, we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1. We find that OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function...
December 28, 2009: Journal of Cell Biology
https://www.readbyqxmd.com/read/19409380/loss-of-drp1-function-alters-opa1-processing-and-changes-mitochondrial-membrane-organization
#18
Kristin Möpert, Petr Hajek, Stephan Frank, Christiane Chen, Jörg Kaufmann, Ansgar Santel
RNAi mediated loss of Drp1 function changes mitochondrial morphology in cultured HeLa and HUVEC cells by shifting the balance of mitochondrial fission and fusion towards unopposed fusion. Over time, inhibition of Drp1 expression results in the formation of a highly branched mitochondrial network along with "bulge"-like structures. These changes in mitochondrial morphology are accompanied by a reduction in levels of Mitofusin 1 (Mfn1) and 2 (Mfn2) and a modified proteolytic processing of OPA1 isoforms, resulting in the inhibition of cell proliferation...
August 1, 2009: Experimental Cell Research
https://www.readbyqxmd.com/read/18076378/metalloprotease-mediated-opa1-processing-is-modulated-by-the-mitochondrial-membrane-potential
#19
Olwenn Guillery, Florence Malka, Thomas Landes, Emmanuelle Guillou, Craig Blackstone, Anne Lombès, Pascale Belenguer, Damien Arnoult, Manuel Rojo
BACKGROUND INFORMATION: Human OPA1 (optic atrophy type 1) is a dynamin-related protein of the mitochondrial IMS (intermembrane space) involved in membrane fusion and remodelling. Similarly to its yeast orthologue Mgm1p that exists in two isoforms generated by the serine protease Pcp1p/Rbd1p, OPA1 exists in various isoforms generated by alternative splicing and processing. In the present paper, we focus on protease processing of OPA1. RESULTS: We find that various mammalian cell types display a similar pattern of OPA1 isoforms [two L-OPA1 (long isoforms of OPA1) and three S-OPA1 (short isoforms of OPA1)] and that loss of the inner membrane potential, but not inhibition of oxidative phosphorylation or glycolysis, induces rapid and complete processing of L-OPA1 to S-OPA1...
May 2008: Biology of the Cell
https://www.readbyqxmd.com/read/17709429/opa1-processing-controls-mitochondrial-fusion-and-is-regulated-by-mrna-splicing-membrane-potential-and-yme1l
#20
Zhiyin Song, Hsiuchen Chen, Maja Fiket, Christiane Alexander, David C Chan
OPA1, a dynamin-related guanosine triphosphatase mutated in dominant optic atrophy, is required for the fusion of mitochondria. Proteolytic cleavage by the mitochondrial processing peptidase generates long isoforms from eight messenger RNA (mRNA) splice forms, whereas further cleavages at protease sites S1 and S2 generate short forms. Using OPA1-null cells, we developed a cellular system to study how individual OPA1 splice forms function in mitochondrial fusion. Only mRNA splice forms that generate a long isoform in addition to one or more short isoforms support substantial mitochondrial fusion activity...
August 27, 2007: Journal of Cell Biology
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