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Aging and Disease Apr 2024Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are... (Review)
Review
Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments.
Topics: Humans; Ferroptosis; Apoptosis; Cardiovascular Diseases; Cell Death; Mitochondria
PubMed: 37548939
DOI: 10.14336/AD.2023.0717 -
International Journal of Biological... 2023N6-methyladenosine (mA) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various...
N6-methyladenosine (mA) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various biological processes. However, its roles in fulminant hepatitis remain largely unknown. In the current study, YTHDF1 expression was found to be significantly downregulated in the livers among patients, as well as murine models with fulminant hepatitis versus normal controls. Thus, we hypothesized that YTHDF1 protects against fulminant hepatitis and investigated the underlying molecular mechanisms. Fulminant hepatitis was induced by D-GalN/LPS in conventional YTHDF1 knockout (YTHDF1) mice, hepatocyte-specific YTHDF1 overexpression (AAV8- YTHDF1) mice, and corresponding control mice. Primary hepatocytes were cultured and subjected to LPS insult . Hepatic histology, cell death, oxidative stress and mitochondrial function were examined to assess liver damage. The molecular mechanisms of YTHDF1 function were explored using multi-omics analysis. Ablation of YTHDF1 exacerbated hepatic apoptosis and reactive oxygen species (ROS) production and increased the number of aberrant mitochondria, while YTHDF1 overexpression resulted in the opposite effects. Multiomics analysis identified MFG-E8 as the direct target of YTHDF1. YTHDF1 augmented the translation of MFG-E8 in an mA-dependent manner without effect on its mRNA expression, thereby restoring mitochondrial function. Additionally, administration of MFG-E8 almost completely reversed the YTHDF1 deficiency-mediated exacerbation of liver injury. The current study suggested that the mA reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an mA-dependent manner.
Topics: Animals; Mice; Apoptosis; Lipopolysaccharides; Massive Hepatic Necrosis; RNA; RNA-Binding Proteins
PubMed: 37564203
DOI: 10.7150/ijbs.84768 -
Cancer Medicine Aug 2023A novel form of cell death termed cuproptosis was proposed recently. miRNAs play important roles in colorectal cancer (CRC). However, their relationships have not been...
BACKGROUND
A novel form of cell death termed cuproptosis was proposed recently. miRNAs play important roles in colorectal cancer (CRC). However, their relationships have not been reported.
METHODS
miRNAs that negatively regulate 16 cuproptosis regulators were predicted using Targetscan database. The univariate Cox, LASSO, and multivariate Cox regression analyses were performed to select cuproptosis-related miRNAs. GSEA and ssGSEA analysis was carried out for functional enrichment analysis. The immune cell proportion score (IPS) and the efficiencies of multiple chemotherapy drugs were compared between different risk groups. The CCK8, cell colony, edu, and flow cytometry assays were performed to validate the roles of miRNA. Luciferase reporter assay confirmed the regulatory mechanism of miRNA on cuproptosis.
RESULTS
Six cuproptosis-related miRNAs (hsa-miR-653, hsa-miR-216a, hsa-miR-3684, hsa-miR-4437, hsa-miR-641, and hsa-miR-552) were screened out for model construction. The risk score could act as an independent prognostic indicator in CRC (p < 0.001, 95% HR = 1.243 (1.129-1.369)). The nomogram could efficiently predict the overall survival rate (AUC = 0.836). Then, the level of immunosuppressive pathways, immunosuppressive cells, stromal-activated genes, and stromal score was higher in the high-risk group. The IPS analysis showed a better response to immunotherapy in the low-risk group. Also, the risk score was closely correlated with efficiencies of multiple chemotherapy drugs. Furthermore, miR-653 was highly expressed in CRC tissues (p < 0.001), closely correlated with T stage (p < 0.001), metastasis (p < 0.001), and tumor stage (p < 0.001). High expression of miR-653 predicted a shorter overall survival (p = 0.0282) and disease-free survival (p = 0.0056). In addition, miR-653 promoted cell proliferation, inhibited apoptosis, and negatively regulated the expression of DLD through directly binding to the 3'-UTR of DLD mRNA.
CONCLUSION
We constructed a cuproptosis-related miRNA signature for the prediction of CRC patient survival and immunotherapy sensitivity. miR-653 was highly expressed in CRC tissues, promoted cell proliferation, and inhibited apoptosis by negatively regulating the expression of DLD.
Topics: Humans; MicroRNAs; Apoptosis; 3' Untranslated Regions; Cell Death; Colorectal Neoplasms
PubMed: 37334893
DOI: 10.1002/cam4.6270 -
Frontiers in Endocrinology 2023As important organelles of energetic and metabolism, changes in the dynamic state of mitochondria affect the homeostasis of cellular metabolism. Mitochondrial dynamics... (Review)
Review
As important organelles of energetic and metabolism, changes in the dynamic state of mitochondria affect the homeostasis of cellular metabolism. Mitochondrial dynamics include mitochondrial fusion and mitochondrial fission. The former is coordinated by mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy 1 (Opa1), and the latter is mediated by dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1) and mitochondrial fission factor (MFF). Mitochondrial fusion and fission are generally in dynamic balance and this balance is important to preserve the proper mitochondrial morphology, function and distribution. Diabetic conditions lead to disturbances in mitochondrial dynamics, which in return causes a series of abnormalities in metabolism, including decreased bioenergy production, excessive production of reactive oxygen species (ROS), defective mitophagy and apoptosis, which are ultimately closely linked to multiple chronic complications of diabetes. Multiple researches have shown that the incidence of diabetic complications is connected with increased mitochondrial fission, for example, there is an excessive mitochondrial fission and impaired mitochondrial fusion in diabetic cardiomyocytes, and that the development of cardiac dysfunction induced by diabetes can be attenuated by inhibiting mitochondrial fission. Therefore, targeting the restoration of mitochondrial dynamics would be a promising therapeutic target within type II diabetes (T2D) and its complications. The molecular approaches to mitochondrial dynamics, their impairment in the context of T2D and its complications, and pharmacological approaches targeting mitochondrial dynamics are discussed in this review and promise benefits for the therapy of T2D and its comorbidities.
Topics: Humans; Diabetes Mellitus, Type 2; Mitochondrial Dynamics; Apoptosis; Homeostasis; Mitochondria
PubMed: 37670891
DOI: 10.3389/fendo.2023.1230168 -
STAR Protocols Sep 2023Mammalian cells can die by apoptosis or by one of several non-apoptotic mechanisms, such as ferroptosis. Here, we present a protocol to distinguish ferroptosis from...
Mammalian cells can die by apoptosis or by one of several non-apoptotic mechanisms, such as ferroptosis. Here, we present a protocol to distinguish ferroptosis from other cell death mechanisms in cultured cells. We describe steps for seeding cells, administering mechanism-specific cell death inducers and inhibitors, and measuring cell death and viability. We then detail the use of molecular markers to verify mechanisms of cell death. This protocol can be used to identify and distinguish ferroptosis in 2D and 3D cultures. For complete details on the use and execution of this protocol, please refer to Ko, et al. (2019), Magtanong, et al. (2022), and Armenta, et al. (2022)..
Topics: Animals; Ferroptosis; Cell Death; Apoptosis; Cells, Cultured; Mammals
PubMed: 37556320
DOI: 10.1016/j.xpro.2023.102457 -
Advanced Science (Weinheim,... Feb 2024Neutrophils, accounting for ≈70% of human peripheral leukocytes, are key cells countering bacterial and fungal infections. Neutrophil homeostasis involves a balance... (Review)
Review
Neutrophils, accounting for ≈70% of human peripheral leukocytes, are key cells countering bacterial and fungal infections. Neutrophil homeostasis involves a balance between cell maturation, migration, aging, and eventual death. Neutrophils undergo different death pathways depending on their interactions with microbes and external environmental cues. Neutrophil death has significant physiological implications and leads to distinct immunological outcomes. This review discusses the multifarious neutrophil death pathways, including apoptosis, NETosis, pyroptosis, necroptosis, and ferroptosis, and outlines their effects on immune responses and disease progression. Understanding the multifaceted aspects of neutrophil death, the intersections among signaling pathways and ramifications of immunity will help facilitate the development of novel therapeutic methods.
Topics: Humans; Neutrophils; Leukocytes; Aging; Apoptosis; Cell Differentiation
PubMed: 38044275
DOI: 10.1002/advs.202306457 -
Biochimie Aug 2023The Wnt/β-catenin signaling pathway is a highly conserved pathway that is involved in cell development, proliferation, differentiation, apoptosis and autophagy. Among... (Review)
Review
The Wnt/β-catenin signaling pathway is a highly conserved pathway that is involved in cell development, proliferation, differentiation, apoptosis and autophagy. Among these processes, apoptosis and autophagy occur physiologically during host defense and the maintenance of intracellular homeostasis. Mounting evidence suggests that the crosstalk between Wnt/β-catenin-regulated apoptosis and autophagy has broad functional significance in various diseases. Herein, we summarize the recent studies in understanding the role of the Wnt/β-catenin signaling pathway in apoptosis and autophagy, and draw the following conclusions: a) For apoptosis, the regulation of Wnt/β-catenin is generally positive. However, a small amount of evidence indicates the presence of a negatively regulated relationship between Wnt/β-catenin and apoptosis; b) Wnt/β-catenin influences the occurrence and development of autophagy by regulating autophagy-related factors, and these factors in turn affect Wnt/β-catenin pathway; c) Wnt/β-catenin always balances the molecular damage caused by the crosstalk between autophagy and apoptosis in a compensatory manner. Understanding the specific role of the Wnt/β-catenin signaling pathway during different stages of autophagy and apoptosis may provide new insights into the progression of related diseases regulated by the Wnt/β-catenin signaling pathway.
Topics: Wnt Signaling Pathway; beta Catenin; Cell Differentiation; Autophagy; Apoptosis; Cell Proliferation
PubMed: 36907502
DOI: 10.1016/j.biochi.2023.03.001 -
European Journal of Medical Research Oct 2023GRP78 is a molecular chaperone protein in the endoplasmic reticulum that is involved in protein assembly and quality control, and it participates in ER stress regulation... (Review)
Review
BACKGROUND
GRP78 is a molecular chaperone protein in the endoplasmic reticulum that is involved in protein assembly and quality control, and it participates in ER stress regulation of endoplasmic reticulum stress pathways. Studies have confirmed that GRP78 gene is highly expressed in a variety of tumors and is involved in different biological functions.
PURPOSE
The present review highlights the involvement of the GRP78 gene in regulating the development of cervical cancer by promoting the proliferation and invasion of cervical cancer cells as well as by inhibiting apoptosis and promoting the Warburg effect. High expression of GRP78 is positively correlated with chemotherapy resistance in cervical cancer. GRP78 plays an anticancer role in cervical cancer by regulating autophagy and apoptosis. Mediated immune CD8 + T cells regulate tumor cell immunity and play a role in the application of the HPV vaccine.
CONCLUSIONS
GRP78 plays a multifunctional role in cervical cancer and has important therapeutic and diagnostic value.
Topics: Female; Humans; Apoptosis; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Uterine Cervical Neoplasms
PubMed: 37858217
DOI: 10.1186/s40001-023-01241-0 -
Frontiers in Immunology 2023During infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO... (Review)
Review
During infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO and fights infection, M2 macrophages are permissive host cells that express arginase 1 and play a role in tissue repair. The regulation of M1 and M2 phenotypes might either induce or impair macrophage-mediated immunity towards parasite control or persistence in chronic Chagas disease. Here, we highlight a key role of macrophage activation in early immune responses to that prevent escalating parasitemia, heart parasitism, and mortality during acute infection. We will discuss the mechanisms of macrophage activation and deactivation, such as T cell cytokines and efferocytosis, and how to improve macrophage-mediated immunity to prevent parasite persistence, inflammation, and the development of chagasic cardiomyopathy. Potential vaccines or therapy must enhance early T cell-macrophage crosstalk and parasite control to restrain the pathogenic outcomes of parasite-induced inflammation in the heart.
Topics: Humans; Macrophages; Chagas Disease; Cytokines; Inflammation; Apoptosis
PubMed: 37662946
DOI: 10.3389/fimmu.2023.1244071 -
International Journal of Molecular... Aug 2023MicroRNAs (miRNAs) are essential regulators of numerous biological processes in animals, including adipogenesis. Despite the abundance of miRNAs associated with...
MicroRNAs (miRNAs) are essential regulators of numerous biological processes in animals, including adipogenesis. Despite the abundance of miRNAs associated with adipogenesis, their exact mechanisms of action remain largely unknown. Our study highlights the role of as a major regulator of adipocyte proliferation, apoptosis, and differentiation. Here, we demonstrated that the expression of initially increased during adipogenesis before decreasing. Overexpression of in adipocytes ultimately inhibited cell proliferation and differentiation, reduced the number of EdU fluorescence-stained cells, increased the number of G1 phase cells, reduced the number of G2 and S phase cells, and downregulated the expression of proliferation markers ( and ) and differentiation markers (, , and ). Additionally, overexpression of promoted the expression of apoptosis-related genes (, , and ), and increased the number of apoptotic cells observed via flow cytometry. In contrast, inhibition in adipocytes yielded opposite effects to those observed during overexpression. Moreover, luciferase reporter assays confirmed as a target gene of , and revealed that downregulates mRNA expression. These findings offer compelling evidence that targets , inhibits proliferation and differentiation, and promotes apoptosis. Therefore, these results offer novel insights into the regulation of adipocyte growth and development.
Topics: Animals; Genes, cdc; Cell Differentiation; Apoptosis; Adipogenesis; Cell Proliferation
PubMed: 37628891
DOI: 10.3390/ijms241612710