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

Forsström, S; Jackson, CB; Carroll, CJ; Kuronen, M; Pirinen, E; Pradhan, S; Marmyleva, A; Auranen, M; Kleine, I-M; Khan, NA; et al. Forsström, S; Jackson, CB; Carroll, CJ; Kuronen, M; Pirinen, E; Pradhan, S; Marmyleva, A; Auranen, M; Kleine, I-M; Khan, NA; Roivainen, A; Marjamäki, P; Liljenbäck, H; Wang, L; Battersby, BJ; 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 Metab, 30 (6). 1040-1054.e7. ISSN 1932-7420 https://doi.org/10.1016/j.cmet.2019.08.019
SGUL Authors: Carroll, Christopher John

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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, mitochondrial 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. Mitochondrial 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.

Item Type: Article
Additional Information: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: FGF21, de novo serine biosynthesis, endocrine signaling, mitochondrial disease, mitochondrial integrated stress response, mitochondrial unfolded protein response, one carbon cycle, stress response, 0601 Biochemistry And Cell Biology, 1101 Medical Biochemistry And Metabolomics, Endocrinology & Metabolism
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Cell Metab
ISSN: 1932-7420
Language: eng
Dates:
DateEvent
3 December 2019Published
12 September 2019Published Online
20 August 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
PubMed ID: 31523008
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111306
Publisher's version: https://doi.org/10.1016/j.cmet.2019.08.019

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