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

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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

Titel: Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions
Författare: Forsström, Saara; Jackson, Christopher B.; Carroll, Christopher J.; Kuronen, Mervi; Pirinen, Eija; Pradhan, Swagat; Marmyleva, Anastasiia; Auranen, Mari; Kleine, Iida-Marja; Khan, Nahid A.; Roivainen, Anne; Marjamäki, Paivi; Liljenbäck, Heidi; Wang, Liya; Battersby, Brendan J.; Richter, Uwe; Velagapudi, Vidya; Nikkanen, Joni; Euro, Liliya; Suomalainen, Anu
Upphovmannens organisation: STEMM - Stem Cells and Metabolism Research Program
Research Programs Unit
Faculty of Medicine
University of Helsinki
Clinicum
CAMM - Research Program for Clinical and Molecular Metabolism
Department of Biochemistry and Developmental Biology
Eija Pirinen / Principal Investigator
HUS Neurocenter
Staff Services
Department of Neurosciences
Institute of Biotechnology
University Management
Molecular and Integrative Biosciences Research Programme
Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
HUSLAB
Anu Wartiovaara / Principal Investigator
Datum: 2019-12-03
Språk: eng
Sidantal: 22
Tillhör serie: Cell Metabolism
ISSN: 1550-4131
DOI: https://doi.org/10.1016/j.cmet.2019.013.019
Permanenta länken (URI): http://hdl.handle.net/10138/322295
Abstrakt: 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.
Subject: MULTIPLE DELETIONS
METABOLIC-ACTIVITY
DNA DELETIONS
BETA-KLOTHO
PPAR-ALPHA
MUSCLE
FGF21
OPA1
ACTIVATION
DEFICIENCIES
3121 General medicine, internal medicine and other clinical medicine
1182 Biochemistry, cell and molecular biology
Referentgranskad: Ja
Användningsbegränsning: openAccess
Parallelpublicerad version: draft


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