Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

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dc.contributor.author Forsström, Saara
dc.contributor.author Jackson, Christopher B.
dc.contributor.author Carroll, Christopher J.
dc.contributor.author Kuronen, Mervi
dc.contributor.author Pirinen, Eija
dc.contributor.author Pradhan, Swagat
dc.contributor.author Marmyleva, Anastasiia
dc.contributor.author Auranen, Mari
dc.contributor.author Kleine, Iida-Marja
dc.contributor.author Khan, Nahid A.
dc.contributor.author Roivainen, Anne
dc.contributor.author Marjamäki, Paivi
dc.contributor.author Liljenbäck, Heidi
dc.contributor.author Wang, Liya
dc.contributor.author Battersby, Brendan J.
dc.contributor.author Richter, Uwe
dc.contributor.author Velagapudi, Vidya
dc.contributor.author Nikkanen, Joni
dc.contributor.author Euro, Liliya
dc.contributor.author Suomalainen, Anu
dc.date.accessioned 2020-12-03T03:32:58Z
dc.date.available 2021-12-18T03:46:02Z
dc.date.issued 2019-12-03
dc.identifier.citation Forsström , S , Jackson , C B , Carroll , C J , Kuronen , M , Pirinen , E , Pradhan , S , Marmyleva , A , Auranen , M , Kleine , I-M , Khan , N A , Roivainen , A , Marjamäki , P , Liljenbäck , H , Wang , L , Battersby , B J , Richter , U , Velagapudi , V , Nikkanen , J , Euro , L & Suomalainen , A 2019 , ' Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions ' , Cell Metabolism , vol. 30 , no. 6 , pp. 1040-+ . https://doi.org/10.1016/j.cmet.2019.013.019
dc.identifier.other PURE: 129674641
dc.identifier.other PURE UUID: 8fdcee9c-0406-4bfc-9d83-ec034247a198
dc.identifier.other WOS: 000500800300007
dc.identifier.other ORCID: /0000-0003-1610-6793/work/67133405
dc.identifier.other ORCID: /0000-0002-3173-6542/work/67134622
dc.identifier.other ORCID: /0000-0003-1035-6417/work/67135424
dc.identifier.other ORCID: /0000-0001-9705-3886/work/67135765
dc.identifier.other ORCID: /0000-0002-0724-6957/work/68614162
dc.identifier.uri http://hdl.handle.net/10138/322295
dc.description.abstract Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease. en
dc.format.extent 22
dc.language.iso eng
dc.relation.ispartof Cell Metabolism
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject MULTIPLE DELETIONS
dc.subject METABOLIC-ACTIVITY
dc.subject DNA DELETIONS
dc.subject BETA-KLOTHO
dc.subject PPAR-ALPHA
dc.subject MUSCLE
dc.subject FGF21
dc.subject OPA1
dc.subject ACTIVATION
dc.subject DEFICIENCIES
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions en
dc.type Article
dc.contributor.organization STEMM - Stem Cells and Metabolism Research Program
dc.contributor.organization Research Programs Unit
dc.contributor.organization Faculty of Medicine
dc.contributor.organization University of Helsinki
dc.contributor.organization Clinicum
dc.contributor.organization CAMM - Research Program for Clinical and Molecular Metabolism
dc.contributor.organization Department of Biochemistry and Developmental Biology
dc.contributor.organization Eija Pirinen / Principal Investigator
dc.contributor.organization HUS Neurocenter
dc.contributor.organization Staff Services
dc.contributor.organization Department of Neurosciences
dc.contributor.organization Institute of Biotechnology
dc.contributor.organization University Management
dc.contributor.organization Molecular and Integrative Biosciences Research Programme
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.contributor.organization HUSLAB
dc.contributor.organization Anu Wartiovaara / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.cmet.2019.013.019
dc.relation.issn 1550-4131
dc.rights.accesslevel openAccess
dc.type.version draft

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