Mitochondrial stress and GDF15 in the pathophysiology of sepsis

Fujita, Yasunori; Ito, Masafumi; Ohsawa, Ikuroh

doi:10.1016/j.abb.2020.108668

“…However, it is unclear whether its upregulation is due to its protective effect or further promotion of disease progression. There were studies reported that GDF15 was elevated in sepsis (13)(14)(15)(16)(17), and Fujita et al reported that the increased GDF15 was a result of mitochondrial stress in sepsis (18).…”

Section: Introductionmentioning

confidence: 99%

“…There were studies reported that GDF15 was elevated in sepsis ( 13 – 17 ), and Fujita et al. reported that the increased GDF15 was a result of mitochondrial stress in sepsis ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Li

¹

,

Tang

²

,

Chen

³

et al. 2021

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Growth differentiation factor 15 (GDF15) is involved in the occurrence and development of many diseases, and there are few studies on its relationship with sepsis. This article aims to explore the clinical value of GDF15 in sepsis and to preliminarily explore its prospective regulatory effect on macrophage inflammation and its functions. We recruited 320 subjects (132 cases in sepsis group, 93 cases in nonsepsis group, and 95 cases in control group), then detected the serum GDF15 levels and laboratory indicators, and further investigated the correlation between GDF15 and laboratory indicators, and also analyzed the clinical value of GDF15 in sepsis diagnosis, severity assessment, and prognosis. In vitro, we used LPS to stimulate THP-1 and RAW264.7 cells to establish the inflammatory model, and detected the expression of GDF15 in the culture medium and cells under the inflammatory state. After that, we added GDF15 recombinant protein (rGDF15) pretreatment to explore its prospective regulatory effect on macrophage inflammation and its functions. The results showed that the serum GDF15 levels were significantly increased in the sepsis group, which was correlated with laboratory indexes of organ damage, coagulation indexes, inflammatory factors, and SOFA score. GDF15 also has a high AUC in the diagnosis of sepsis, which can be further improved by combining with other indicators. The dynamic monitoring of GDF15 levels can play an important role in the judgment and prognosis of sepsis. In the inflammatory state, the expression of intracellular and extracellular GDF15 increased. GDF15 can reduce the levels of cytokines, inhibit M1 polarization induced by LPS, and promote M2 polarization. Moreover, GDF15 also enhances the phagocytosis and bactericidal function of macrophages. Finally, we observed a decreased level of the phosphorylation of JAK1/STAT3 signaling pathway and the nuclear translocation of NF-κB p65 with the pretreatment of rGDF15. In summary, our study found that GDF15 has good clinical application value in sepsis and plays a protective role in the development of sepsis by regulating the functions of macrophages and inhibiting the activation of JAK1/STAT3 pathway and nuclear translocation of NF-κB p65.

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“…Mitochondria could represent an important target for intervention in cardiovascular health [42]. On the one hand, GDF-15 was related to mitochondrial dysfunction closely [43,44]. On the other hand, GDF-15 showed a linear correlation with FRS after adjusting for other cardiovascular risk factors.…”

Section: Association Between Gdf-15 and Cardiovascular Riskmentioning

confidence: 97%

Association between Growth Differentiation Factor-15 and Risk of Cardiovascular Diseases in Patients with Adult Growth Hormone Deficiency

Wu

¹

,

Wang

²

,

Ren

³

et al. 2021

International Journal of Endocrinology

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Objective. Patients with adult growth hormone deficiency (AGHD) confer a heightened risk of cardiovascular disease and increased mortality because of metabolic disorders. Growth differentiation factor-15 (GDF-15) plays an important role in predicting metabolic abnormalities. We sought to investigate the correlation between GDF-15 and cardiovascular risk in AGHD patients. Methods. The study enrolled 80 AGHD patients and 80 healthy subjects. We analyzed the association between GDF-15 and some major biochemical indicators. The potential association between GDF-15 and cardiovascular disease risk was analyzed. Results. The AGHD group exhibited increased waist-hip ratio and high-sensitivity C-reactive protein (hs-CRP) and lipid levels compared with the healthy control group. Serum GDF-15 levels in AGHD group were elevated significantly compared with the control group P < 0.001 . GDF-15 levels were negatively associated with insulin-like growth factor-1 in AGHD group P = 0.006 and positively correlated with waist-to-hip ratio P = 0.018 , triglycerides P = 0.007 , and hs-CRP P = 0.046 . In addition, GDF-15 was positively correlated with Framingham risk score significantly after adjustment for other factors (r = 0.497, P < 0.001 ). Moreover, GDF-15 was an independent risk factor for cardiovascular disease in AGHD patients after adjusting for traditional cardiovascular risk factors. Conclusion. Elevated GDF-15 levels were significantly associated with cardiovascular risk factors and can be considered as a predictive biomarker of cardiovascular risk in AGHD patients.

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“…The most notable changes were observed in the HAC15 and WM266-4 cell lines [CDK2, ~0. cell line, mitotane significantly stimulated the expression of growth differentiation factor 15 (fold-change=27.38), a major secretory protein induced by mitochondrial dysfunction (48), and DNA damage inducible transcript 3 (DDIT3; fold-change=8.07), an endoplasmic reticulum stress-induced apoptosis factor (49). In HAC15 cells, mitotane most potently inhibited the expression of genes involved in adrenal steroidogenesis, such as low-density lipoprotein receptor (fold-change=-4.97).…”

Section: Mitotane At a Dose Of 50 µM Leads To Necrosis And Cell Cycle...mentioning

confidence: 99%

Biological response of adrenal carcinoma and melanoma cells to mitotane treatment

Stelcer

¹

,

Komarowska

²

,

Jopek

³

et al. 2022

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A previous case report described an adrenal incidentaloma initially misdiagnosed as adrenocortical carcinoma (ACC), which was treated with mitotane. The final diagnosis was metastatic melanoma of unknown primary origin. However, the patient developed rapid disease progression after mitotane withdrawal, suggesting a protective role for mitotane in a non-adrenal-derived tumor. The aim of the present study was to determine the biological response of primary melanoma cells obtained from that patient, and that of other established melanoma and ACC cell lines, to mitotane treatment using a proliferation assay, flow cytometry, quantitative PCR and microarrays. Although mitotane inhibited the proliferation of both ACC and melanoma cells, its role in melanoma treatment appears to be limited. Flow cytometry analysis and transcriptomic studies indicated that the ACC cell line was highly responsive to mitotane treatment, while the primary melanoma cells showed a moderate response in vitro. Mitotane modified the activity of several key biological processes, including 'mitotic nuclear division', 'DNA repair', 'angiogenesis' and 'negative regulation of ERK1 and ERK2 cascade'. Mitotane administration led to elevated levels of DNA double-strand breaks, necrosis and apoptosis. The present study provides a comprehensive insight into the biological response of mitotane-treated cells at the molecular level. Notably, the present findings offer new knowledge on the effects of mitotane on ACC and melanoma cells.

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Mitochondrial stress and GDF15 in the pathophysiology of sepsis

Cited by 28 publications

References 133 publications

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Association between Growth Differentiation Factor-15 and Risk of Cardiovascular Diseases in Patients with Adult Growth Hormone Deficiency

Biological response of adrenal carcinoma and melanoma cells to mitotane treatment

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