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GDF15 as a central mediator for integrated stress response and a promising therapeutic molecule for metabolic disorders and NASH

Authors
 Kook Hwan Kim  ;  Myung-Shik Lee 
Citation
 BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, Vol.1865(3) : 129834, 2020-12 
Journal Title
 BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS 
ISSN
 0304-4165 
Issue Date
2020-12
Keywords
ER ; GDF15 ; Metabolic diseases ; Mitochondria ; NASH ; Stress
Abstract
Background: Mitochondria is a key organelle for energy production and cellular adaptive response to intracellular and extracellular stresses. Mitochondrial stress can be evoked by various stimuli such as metabolic stressors or pathogen infection, which may lead to expression of 'mitokines' such as growth differentiation factor 15 (GDF15). Scope of review: This review summarizes the mechanism of GDF15 expression in response to organelle stress such as mitochondrial stress, and covers pathophysiological conditions or diseases that are associated with elevated GDF15 level. This review also illustrates the in vivo role of GDF15 expression in those stress conditions or diseases, and a potential of GDF15 as a therapeutic agent against metabolic disorders such as NASH. Major conclusions: Mitochondrial unfolded protein response (UPRmt) is a critical process to recover from mitochondrial stress. UPRmt can induce expression of secretory proteins that can exert systemic effects (mitokines) as well as mitochondrial chaperons. GDF15 can have either protective or detrimental systemic effects in response to mitochondrial stresses, suggesting its role as a mitokine. Mounting evidence shows that GDF15 is also induced by stresses of organelles other than mitochondria such as endoplasmic reticulum (ER). GDF15 level is increased in serum or tissue of mice and human subjects with metabolic diseases such as obesity or NASH. GDF15 can modulate metabolic features of those diseases. General significance: GDF15 play a role as an integrated stress response (ISR) beyond mitochondrial stress response. GDF15 is involved in the pathogenesis of metabolic diseases such as NASH, and also could be a candidate for therapeutic agent against those diseases.
Full Text
https://www.sciencedirect.com/science/article/pii/S0304416520303457
DOI
10.1016/j.bbagen.2020.129834
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/181498
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