GDF15 as a key disease target and biomarker: linking chronic lung diseases and ageing

Abstract

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, is expressed in several human organs. In particular, it is highly expressed in the placenta, prostate, and liver. The expression of GDF15 increases under cellular stress and pathological conditions. Although numerous transcription factors directly up-regulate the expression of GDF15, the receptors and downstream mediators of GDF15 signal transduction in most tissues have not yet been determined. Glial cell-derived neurotrophic factor family receptor α-like protein was recently identified as a specific receptor that plays a mediating role in anorexia. However, the specific receptors of GDF15 in other tissues and organs remain unclear. As a marker of cell stress, GDF15 appears to exert different effects under different pathological conditions. Cell senescence may be an important pathogenetic process and could be used to assess the progression of various lung diseases, including COVID-19. As a key member of the senescence-associated secretory phenotype protein repertoire, GDF15 seems to be associated with mitochondrial dysfunction, although the specific molecular mechanism linking GDF15 expression with ageing remains to be elucidated. Here, we focus on research progress linking GDF15 expression with the pathogenesis of various chronic lung diseases, including neonatal bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and pulmonary hypertension, suggesting that GDF15 may be a key biomarker for diagnosis and prognosis. Thus, in this review, we aimed to provide new insights into the molecular biological mechanism and emerging clinical data associated with GDF15 in lung-related diseases, while highlighting promising research and clinical prospects.

Keywords: Chronic lung disease; GDF15; Mitochondrial dysfunction; SASP; Senescence.

Fig. 1

Human GDF15 includes 2 exons and 1 intron. Inactive human GDF15 pre-pro-protein in the cytoplasm is dimerised by a specific disulphide bond, cleaved at the RXXR cleavage site in the Golgi apparatus, and secreted as mature GDF15. PCSK: Proprotein convertase subtilisin/kexin; MMP: Matrix metalloproteinase

Fig. 2

Overview of regulation of GDF15 expression. PPAR-γ: Peroxisome proliferator-activated receptor γ; NSAID: Non-steroidal anti-inflammatory drugs; P53: Tumour protein 53; Sp1: Specificity protein 1; COUP-TF1: COUP transcription factor 1; ATF: Activating transcription factor; CHOP: C/EBP homologous protein; NF-κB: Nuclear factor-κB; UPR^mt: Mitochondrial unfolded protein response; ER: Endoplasmic reticulum