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

Dec 28, 2020Biochimica et biophysica acta. General subjects

GDF15's role in stress response and its potential as treatment for metabolic diseases and fatty liver

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Abstract

GDF15 levels are increased in serum or tissue of mice and human subjects with metabolic diseases such as obesity and NASH.

Mitochondrial stress can trigger the expression of GDF15, a type of signaling protein.
The mitochondrial unfolded protein response (UPRmt) is essential for recovery from mitochondrial stress.
GDF15 may have both protective and harmful effects on the body in response to mitochondrial stress.
Evidence suggests that GDF15 is also produced in response to stress in organelles other than mitochondria.
GDF15 could influence metabolic features of diseases like obesity and NASH.

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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.

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

Abstract

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