Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system

Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	Cell metabolism Ročník 19; číslo 4; s. 642
Hlavní autori:	Segref, Alexandra, Kevei, Éva, Pokrzywa, Wojciech, Schmeisser, Kathrin, Mansfeld, Johannes, Livnat-Levanon, Nurit, Ensenauer, Regina, Glickman, Michael H, Ristow, Michael, Hoppe, Thorsten
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.04.2014
Predmet:	Adenosine Triphosphate - metabolism Animals Animals, Genetically Modified Caenorhabditis elegans Cell Line Cyclooxygenase 1 - genetics Electrophoresis, Polyacrylamide Gel Green Fluorescent Proteins Humans Immunoblotting Mitochondrial Diseases - metabolism Mitochondrial Diseases - physiopathology Mutagenesis Organic Chemicals Oxidative Phosphorylation Proteasome Endopeptidase Complex - metabolism Proteolysis Reactive Oxygen Species - metabolism Ubiquitin - metabolism Ubiquitin-Protein Ligases - metabolism
ISSN:	1932-7420, 1932-7420
On-line prístup:	Zistit podrobnosti o prístupe
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Abstract	Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention.
AbstractList	Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention. Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention.Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention.
Author	Pokrzywa, Wojciech Segref, Alexandra Ristow, Michael Ensenauer, Regina Livnat-Levanon, Nurit Hoppe, Thorsten Glickman, Michael H Kevei, Éva Mansfeld, Johannes Schmeisser, Kathrin
Author_xml	– sequence: 1 givenname: Alexandra surname: Segref fullname: Segref, Alexandra organization: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany – sequence: 2 givenname: Éva surname: Kevei fullname: Kevei, Éva organization: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany – sequence: 3 givenname: Wojciech surname: Pokrzywa fullname: Pokrzywa, Wojciech organization: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany – sequence: 4 givenname: Kathrin surname: Schmeisser fullname: Schmeisser, Kathrin organization: Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany – sequence: 5 givenname: Johannes surname: Mansfeld fullname: Mansfeld, Johannes organization: Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany; Energy Metabolism Laboratory, ETH Zürich, Schwerzenbach/Zürich, CH 8603, Switzerland – sequence: 6 givenname: Nurit surname: Livnat-Levanon fullname: Livnat-Levanon, Nurit organization: Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel – sequence: 7 givenname: Regina surname: Ensenauer fullname: Ensenauer, Regina organization: Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany – sequence: 8 givenname: Michael H surname: Glickman fullname: Glickman, Michael H organization: Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel – sequence: 9 givenname: Michael surname: Ristow fullname: Ristow, Michael organization: Department of Human Nutrition, Institute of Nutrition, University of Jena, 07743 Jena, Germany; Energy Metabolism Laboratory, ETH Zürich, Schwerzenbach/Zürich, CH 8603, Switzerland – sequence: 10 givenname: Thorsten surname: Hoppe fullname: Hoppe, Thorsten email: thorsten.hoppe@uni-koeln.de organization: Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany. Electronic address: thorsten.hoppe@uni-koeln.de
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/24703696$$D View this record in MEDLINE/PubMed
BookMark	eNpNkFtLxDAQhYMo7kX_gA-SR1-2m6SXNI-yeIMFfdDnkiazNkvT7DaJ0H9vxBWEYeaDOXM4zAKdD24AhG4oySih1XqfKQshY4QWGaGpqjM0pyJnK14wcv6PZ2jh_Z6QvMpFfolmrOCJRTVHhzcZOvcJA3jjsdvhLlo5YGuCU50b9Ghkj7XxID14nCTW6djLABq3Ex5BR5VQqmC-TJh-DEIHOLbmGE0ww_owupBunQXsJx_AXqGLnew9XJ_mEn08Prxvnlfb16eXzf12pYqqCiuohWxzrThlrSKiFULmvMjLesdIapxIzqmkacV4xWmpagJlqURdcMUU02yJ7n59U4JjBB8aa7yCvpcDuOgbWtKiYIKWdZLenqSxtaCbw2isHKfm70vsG528bhA
CitedBy_id	crossref_primary_10_3390_cancers12092357 crossref_primary_10_1016_j_tcb_2017_02_007 crossref_primary_10_1371_journal_pgen_1004968 crossref_primary_10_1007_s00438_020_01721_6 crossref_primary_10_3390_ijms18010165 crossref_primary_10_3390_cells12020234 crossref_primary_10_1038_emm_2014_122 crossref_primary_10_1016_j_bbadis_2023_166767 crossref_primary_10_1016_j_ceb_2015_08_004 crossref_primary_10_1155_2016_4350965 crossref_primary_10_1371_journal_pbio_3002543 crossref_primary_10_3389_fncel_2024_1422362 crossref_primary_10_1016_j_cophys_2018_02_010 crossref_primary_10_1038_cddis_2014_477 crossref_primary_10_1038_srep39884 crossref_primary_10_1093_femsyr_fov061 crossref_primary_10_1016_j_tcb_2016_03_002 crossref_primary_10_1016_j_pharmthera_2020_107526 crossref_primary_10_1016_j_freeradbiomed_2018_10_446 crossref_primary_10_1016_j_jep_2020_112839 crossref_primary_10_1016_j_arr_2018_11_006 crossref_primary_10_1016_j_freeradbiomed_2019_11_021 crossref_primary_10_1038_nsmb_2806 crossref_primary_10_1038_srep06571 crossref_primary_10_1073_pnas_1912531117 crossref_primary_10_1111_acel_13710 crossref_primary_10_3389_fcell_2023_1127618 crossref_primary_10_1002_mnfr_201600576 crossref_primary_10_1016_j_tem_2018_03_007 crossref_primary_10_3389_fnmol_2015_00008 crossref_primary_10_1038_s41467_022_33467_7 crossref_primary_10_3390_ijms160819458 crossref_primary_10_1002_cbic_201700006 crossref_primary_10_1534_g3_116_031666 crossref_primary_10_1038_s41598_021_96540_z crossref_primary_10_1016_j_neuint_2017_07_008 crossref_primary_10_1074_jbc_RA120_015162 crossref_primary_10_1371_journal_pgen_1006133 crossref_primary_10_7554_eLife_44425 crossref_primary_10_3390_antiox10040572 crossref_primary_10_1111_acel_13725 crossref_primary_10_3389_fonc_2021_797265 crossref_primary_10_1002_1873_3468_12087 crossref_primary_10_1534_g3_114_015321 crossref_primary_10_1002_acn3_158 crossref_primary_10_1016_j_freeradbiomed_2015_05_041 crossref_primary_10_1111_acel_12431 crossref_primary_10_1002_jcsm_13134 crossref_primary_10_1016_j_yexcr_2020_112093 crossref_primary_10_1371_journal_pone_0187424 crossref_primary_10_1038_s41467_023_37836_8 crossref_primary_10_1038_s41380_020_0807_4 crossref_primary_10_15252_emmm_201809582 crossref_primary_10_1016_j_phrs_2024_107180 crossref_primary_10_1007_s00726_015_2053_7 crossref_primary_10_1111_andr_12991 crossref_primary_10_1007_s12268_014_0509_z crossref_primary_10_1016_j_celrep_2023_112880 crossref_primary_10_1016_j_cell_2019_03_035 crossref_primary_10_1016_j_devcel_2020_06_038 crossref_primary_10_1016_j_exger_2014_11_010 crossref_primary_10_1016_j_phrs_2020_105248 crossref_primary_10_1083_jcb_201702058 crossref_primary_10_1016_j_tox_2016_04_010 crossref_primary_10_1137_22M1487801 crossref_primary_10_1016_j_ajhg_2025_01_001 crossref_primary_10_1016_j_tibs_2017_05_002 crossref_primary_10_1038_cddis_2016_315 crossref_primary_10_1007_s00439_024_02647_4 crossref_primary_10_1016_j_bbadis_2025_167983 crossref_primary_10_1093_femsyr_foy088 crossref_primary_10_3389_fcell_2020_00270 crossref_primary_10_1091_mbc_E18_10_0628 crossref_primary_10_1534_genetics_120_301283 crossref_primary_10_1007_s12223_025_01277_1 crossref_primary_10_1098_rsob_170007 crossref_primary_10_1371_journal_pgen_1006517 crossref_primary_10_1038_nature14859
ContentType	Journal Article
Copyright	Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright_xml	– notice: Copyright © 2014 Elsevier Inc. All rights reserved.
DBID	CGR CUY CVF ECM EIF NPM 7X8
DOI	10.1016/j.cmet.2014.01.016
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic
DatabaseTitleList	MEDLINE MEDLINE - Academic
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database
DeliveryMethod	no_fulltext_linktorsrc
Discipline	Biology
EISSN	1932-7420
ExternalDocumentID	24703696
Genre	Research Support, Non-U.S. Gov't Journal Article Research Support, N.I.H., Extramural
GrantInformation_xml	– fundername: NIH HHS grantid: P40 OD010440
GroupedDBID	--- --K 0R~ 1~5 29B 2WC 4.4 457 4G. 53G 5GY 62- 6J9 7-5 AAEDT AAEDW AAKRW AAKUH AALRI AAMRU AAVLU AAXUO AAYWO ABDGV ABJNI ABMAC ACGFO ACGFS ACVFH ADBBV ADCNI ADEZE ADVLN AEFWE AENEX AEUPX AEXQZ AFPUW AFTJW AGCQF AGHFR AGKMS AIGII AITUG AKAPO AKBMS AKRWK AKYEP ALMA_UNASSIGNED_HOLDINGS AMRAJ APXCP ASPBG AVWKF AZFZN BAWUL CGR CS3 CUY CVF DIK DU5 E3Z EBS ECM EFKBS EIF EJD F5P FCP FDB FEDTE FIRID HVGLF IHE IXB J1W JIG M3Z M41 NPM O-L O9- OK1 P2P RIG ROL RPZ SES SSZ TR2 UNMZH 7X8
ID	FETCH-LOGICAL-c466t-e89ab3dc712bc09b99a374358f2058f70a771a1c09276715c80e55c9847c2c2d2
IEDL.DBID	7X8
ISICitedReferencesCount	92
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000333751600011&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	1932-7420
IngestDate	Thu Oct 02 06:54:31 EDT 2025 Mon Jul 21 06:01:34 EDT 2025
IsDoiOpenAccess	false
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Issue	4
Language	English
License	Copyright © 2014 Elsevier Inc. All rights reserved.
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c466t-e89ab3dc712bc09b99a374358f2058f70a771a1c09276715c80e55c9847c2c2d2
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
OpenAccessLink	http://www.cell.com/article/S1550413114000229/pdf
PMID	24703696
PQID	1514429158
PQPubID	23479
ParticipantIDs	proquest_miscellaneous_1514429158 pubmed_primary_24703696
PublicationCentury	2000
PublicationDate	2014-Apr-01 20140401
PublicationDateYYYYMMDD	2014-04-01
PublicationDate_xml	– month: 04 year: 2014 text: 2014-Apr-01 day: 01
PublicationDecade	2010
PublicationPlace	United States
PublicationPlace_xml	– name: United States
PublicationTitle	Cell metabolism
PublicationTitleAlternate	Cell Metab
PublicationYear	2014
SSID	ssj0036393
Score	2.4491854
Snippet	Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of...
SourceID	proquest pubmed
SourceType	Aggregation Database Index Database
StartPage	642
SubjectTerms	Adenosine Triphosphate - metabolism Animals Animals, Genetically Modified Caenorhabditis elegans Cell Line Cyclooxygenase 1 - genetics Electrophoresis, Polyacrylamide Gel Green Fluorescent Proteins Humans Immunoblotting Mitochondrial Diseases - metabolism Mitochondrial Diseases - physiopathology Mutagenesis Organic Chemicals Oxidative Phosphorylation Proteasome Endopeptidase Complex - metabolism Proteolysis Reactive Oxygen Species - metabolism Ubiquitin - metabolism Ubiquitin-Protein Ligases - metabolism
Title	Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system
URI	https://www.ncbi.nlm.nih.gov/pubmed/24703696 https://www.proquest.com/docview/1514429158
Volume	19
WOSCitedRecordID	wos000333751600011&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText
inHoldings	1
isFullTextHit
isPrint
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LS8QwEA7qKnjx_VhfRPBabNOkSU8i4uJBlz2o7G1J0lR62HZ3uyvsv3em6epJELyUQh-UZDLzNd_MfITcKAhjPDJxkGdhGHDnRKAdV4FxTkuW65w1Va7vz7LfV8NhOmg33Oo2rXLlExtHnVUW98hvITJx8J2RUHeTaYCqUciuthIa66QTA5RBq5bDbxYhhugbe1YZUCRnYVs04_O77NhhLmXEm7adUfI7xGxCTW_3vx-5R3ZakEnvvVXskzVXHpAtLzu5PCSTAcC-6gO9XFHTKqeNUB8dw-IGZ1hmaJO0ZW5qCreMqwxVvlxGzZLOsNkrnGJFBApP4AsARdKFKaaLYu6r-8B06mrsqG8UfUTeeo-vD09Bq7wQWJ4k88CpVJs4szJixoapSVMdA9QQKmchHGSopYx0BJeYTGQkrAqdEDaFUGeZZRk7JhtlVbpTQl0iM2wTyJzQ3AplEqOMFCZG_g_-fbrkejWUI7BspCt06apFPfoZzC458fMxmvgWHCPGsXFYmpz94elzso3T7NNtLkgnh3XtLsmm_ZwX9eyqMRk49gcvX9YxzK8
linkProvider	ProQuest
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Pathogenesis+of+human+mitochondrial+diseases+is+modulated+by+reduced+activity+of+the+ubiquitin%2Fproteasome+system&rft.jtitle=Cell+metabolism&rft.au=Segref%2C+Alexandra&rft.au=Kevei%2C+%C3%89va&rft.au=Pokrzywa%2C+Wojciech&rft.au=Schmeisser%2C+Kathrin&rft.date=2014-04-01&rft.issn=1932-7420&rft.eissn=1932-7420&rft.volume=19&rft.issue=4&rft.spage=642&rft_id=info:doi/10.1016%2Fj.cmet.2014.01.016&rft.externalDBID=NO_FULL_TEXT
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1932-7420&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1932-7420&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1932-7420&client=summon