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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 3; p. 129834
• Main Authors: Kim, Kook Hwan, Lee, Myung-Shik
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2021
• Subjects: Aging - genetics; Aging - metabolism; Animals; blood serum; Disease Models, Animal; endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - genetics; energy; GDF15; Gene Expression Regulation; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Growth Differentiation Factor 15 - therapeutic use; Humans; Metabolic diseases; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; Mitochondrial Myopathies - pathology; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; NASH; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; pathogenesis; pathogens; Stress; stress response; therapeutics; Unfolded Protein Response; Metabolic diseases; Mitochondria; NASH; GDF15; ER; Stress
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129834

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). 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. 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. 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. •UPRmt induces gene expression of GDF15 as a mitokine.•GDF15 plays a role as a protective signal in response to mitochondrial stresses.•GDF15 is a therapeutic candidate against mitochondrial dysfunction-related diseases.