Mitochondrial quality control in human health and disease.

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma.

BACKGROUND: As one of the common subtypes of non-small lung cancer, lung squamous cell carcinoma (LUSC) patients with advanced stage have few choices of treatment strategies. Therefore, it is urgent to discover genes that are associated with the survival and efficacy of immunotherapies. METHOD: Differential gene expression analyses were conducted using TCGA LUSC bulk-sequencing and single-cell RNA-sequencing data. Prognostic genes were identified from the TCGA LUSC cohort. Protein expression validation and survival analyses were performed. Experiments were conducted to explore the underlying mechanisms. In addition, the correlation between gene expression and pathological response to adjuvant immunochemotherapy was also investigated. RESULTS: After a series of bioinformatic analyses, solute carrier family 2 member 1(SLC2A1), encoding glucose transporter-1 (GLUT1), was found to be differentially expressed between tumor and normal tissues. GLUT1 was subsequently identified as an independent prognostic factor for LUSC. GSEA analysis revealed the glycolysis metabolism pathway of KEGG enriched in SLC2A1high tumor tissues. LASSO analyses revealed that tumor tissues with high expression of SLC2A1 were associated with high levels of protein lactylation. We found that SLC2A1 was preferentially expressed by SPP1+ macrophages in the tumor microenvironment, and the expression of SLC2A1 was associated with the abundance of SPP1+ macrophages. Immunofluorescence demonstrated GLUT1 and HIF1α colocalization in tumor-infiltrating macrophages. In vitro experiments showed HIF-1α-induced macrophage polarization under hypoxia, and GLUT1 inhibition blocked this polarization. In addition, SLC2A1 was negatively associated with the common immune checkpoint molecules, such as programmed cell death 1(PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte associated protein 4 (CTLA4) and lymphocyte activating 3 (LAG3), while showed a positive association with CD44. Finally, we observed that there was a significant correlation between pre-adjuvant-treatment GLUT1 expression and the pathological response. CONCLUSION: SLC2A1 expression was differentially upregulated in tumor tissues, and elevated GLUT1 expression was associated with worse survival and poor pathological response to adjuvant immunochemotherapy. Upregulation of GLUT1 promoted macrophage polarization into the M2 phenotype. The findings will contribute to guiding the treatment selection for LUSC patients and providing personalized immunotherapy strategies.

Comprehensive analysis of m6A modification in lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: N6-Methyladenosine (m6A) methylation is the most prevalent post-transcriptional modification in mRNA, and plays significant roles in various diseases. Nevertheless, the precise functions of m6A modification in the formation of ALI remain unclear. In this study we explore the transcriptome distribution of m6A methylation and its probable roles of in ALI. METHODS: Lipopolysaccharide (LPS) was utilized to establish an ALI mouse model. Real-time qPCR, Western blotting and m6A dot blot were utilized to assess m6A methylation level and the expression of m6A methylation enzymes. MeRIP-Seq and RNA-seq were utilized to explore differential m6A modifications and differentially expressed genes in ALI mice. The hub genes and enriched pathways were assessed by Real-time qPCR and Western blotting. RESULTS: Our findings showed that overall m6A methylation level was increased in ALI mice lung tissues, accompanied by lower levels of METTL3 and FTO. Notably, the protein expression of these methylases were different in various cells. There were 772 differently expressed m6A peaks in ALI as compared to the control group, with 316 being hypermethylated and 456 being hypomethylated. GO and KEGG analyses demonstrated these differentially methylated genes were associated with the calcium signaling pathway and cAMP signaling pathway. Furthermore, we identified 50 genes with distinct m6A peaks and mRNA expressions by combined analysis of MeRIP-Seq and RNA-Seq. KEGG analysis also demonstrated that these overlapped genes were closely associated with the calcium signaling pathway, cGMP-PKG signaling pathway, etc. Besides, Western blotting results demonstrated that the protein expression of Fibronectin leucine-rich transmembrane protein 3 (Flrt3) as well as the calcium signaling pathway and cGMP-PKG signaling pathway, increased significantly after ALI. CONCLUSIONS: m6A modification was paramount in the pathogenesis of ALI, and provided a foundation for the further investigation in the prevention and treatment of ALI.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics.

As a multi-substrate transmembrane protease, γ-secretase exists widely in various cells. It controls multiple important cellular activities through substrate cleavage. γ-secretase inhibitors (GSIs) play a role in cancer inhibition by blocking Notch cleavage, and are considered as potential therapeutic strategies for cancer. Currently, GSIs have encouraging performance in preclinical models, yet this success does not translate well in clinical trials. In recent years, a number of breakthrough discoveries have shown us the promise of targeting γ-secretase for the treatment of cancer. Here, we integrate a large amount of data from γ-secretase and its inhibitors and cancer in nearly 30 years, comb and discuss the close connection between γ-secretase and cancer, as well as the potential and problems of current GSIs in cancer treatment. We analyze the possible reasons for the failure performance of current GSIs in clinical trials, and make recommendations for future research areas.

Eriocitrin inhibits epithelial-mesenchymal transformation (EMT) in lung adenocarcinoma cells via triggering ferroptosis.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most prevalent pathological subtype of non-small cell lung cancer (NSCLC), characterized by a high propensity for relapse and metastasis due to epithelial-mesenchymal transition (EMT) of cancer cells. Ferroptosis, a newly discovered regulated cell death modality, is interconnected with the EMT process in certain cancers. Eriocitrin, a natural flavonoid compound, exerts anti-inflammatory and anticancer effects. OBJECTIVES: The aim of this study is to investigate the potential inhibitory effect of eriocitrin on lung adenocarcinoma metastasis and explore whether its underlying mechanism involves ferroptosis induction in cancer cells. METHODS: The CCK8 assay and wound healing assay and transwell were conducted to determine the cell viability and migration ability of A549 and H1299 cells, respectively. EMT process was assessed by western blot and RT-PCR to detect protein and mRNA levels of EMT markers. ROS and cell iron were measured to determine ferroptosis level. RESULTS: Eriocitrin treatment significantly inhibited cell viability and migration ability in a concentration-dependent manner. Furthermore, eriocitrin administration for 24 hours resulted in enhanced expression of E-cadherin, while downregulating vimentin, N-cadherin and snail expression, indicating marked repression of the EMT process. Additionally, eriocitrin significantly induced ferroptosis in A549 and H1299 cells, as evidenced by increased ROS levels, downregulation of Nrf-2, SLC7A11 and GPX4 expression, and enhanced cellular iron accumulation. Moreover, pretreatment with the ferroptosis inhibitor ferrostatin-1 effectively abrogated the inhibitory effects of eriocitrin on EMT. CONCLUSIONS: Our findings further support the anti-cancer properties of eriocitrin, as evidenced by its ability to inhibit the EMT process in LUAD cells, which is partially mediated through induction of ferroptosis in cancer cells.

Pretreatment with Kahweol Attenuates Sepsis-Induced Acute Lung Injury via Improving Mitochondrial Homeostasis in a CaMKKII/AMPK-Dependent Pathway.

SCOPE: It is well-established that dysregulated mitochondrial homeostasis in macrophages leads to inflammation, oxidative stress, and tissue damage, which are essential in the pathogenesis of sepsis-induced acute lung injury (ALI). Kahweol, a natural diterpene extracted from coffee beans, reportedly possesses anti-inflammatory and mitochondrial protective properties. Herein, the study investigates whether Kahweol can alleviate sepsis-induced ALI and explore the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are intraperitoneally injected with lipopolysaccharide (LPS) for 12 h to induce ALI. Pretreatment with kahweol by gavage for 5 days significantly alleviates lung pathological injury, inflammation, and oxidative stress, accompanied by shifting the dynamic process of mitochondria from fission to fusion, enhancing mitophagy, and activating AMPK. To investigate the underlying molecular mechanisms, differentiated THP-1 cells are cultured in a medium containing Kahweol for 12 h prior to LPS exposure, yielding consistent findings with the in vivo results. Moreover, AMPK inhibitors abrogate the above effects, indicating Kahweol acts in an AMPK-dependent manner. Furthermore, the study explores how Kahweol activates AMPK and finds that this process is mediated by CamKK II. CONCLUSION: Pretreatment with Kahweol attenuates sepsis-induced acute lung injury via improving mitochondrial homeostasis in a CaMKKII/AMPK-dependent pathway and may be a potential candidate to prevent sepsis-induced ALI.

HDAC3 promotes macrophage pyroptosis via regulating histone deacetylation in acute lung injury.

Activated inflammation and pyroptosis in macrophage are closely associated with acute lung injury (ALI). Histone deacetylase 3 (HDAC3) serves as an important enzyme that could repress gene expression by mediating chromatin remodeling. In this study, we found that HDAC3 was highly expressed in lung tissues of lipopolysaccharide (LPS)-treated mice. Lung tissues from macrophage HDAC3-deficient mice stimulated with LPS showed alleviative lung pathological injury and inflammatory response. HDAC3 silencing significantly blocked the activation of cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in LPS-induced macrophage. LPS could recruit HDAC3 and H3K9Ac to the miR-4767 gene promoter, which repressed the expression of miR-4767 to promote the expression of cGAS. Taken together, our findings demonstrated that HDAC3 played a pivotal role in mediating pyroptosis in macrophage and ALI by activating cGAS/STING pathway through its histone deacetylation function. Targeting HDAC3 in macrophage may provide a new therapeutic target for the prevention of LPS-induced ALI.

Identification of an inflammatory response signature associated with prognostic stratification and drug sensitivity in lung adenocarcinoma.

Increasing evidence has confirmed the close connection between inflammatory response and tumorigenesis. However, the relationship between inflammatory response genes (IRGs) and the prognosis of lung adenocarcinoma (LUAD) as well as the response to drug therapy remains poorly investigated. Here, we comprehensively analyzed IRGs RNA expression profiling and clinical features of over 2000 LUAD patients from 12 public datasets. The Cox regression method and LASSO analysis were combined to develop a novel IRG signature for risk stratification and drug efficacy prediction in LUAD patients. Enriched pathways, tumor microenvironment (TME), genomic and somatic mutation landscape in different subgroups were evaluated and compared with each other. This established IRG signature including 11 IRGs (ADM, GPC3, IL7R, NMI, NMURI, PSEN1, PTPRE, PVR, SEMA4D, SERPINE1, SPHK1), could well categorize patients into significantly different prognostic subgroups, and have better predictive in independently assessing survival as compared to a single clinical factor. High IRG scores (IRGS) patients might benefit more from immunotherapy and chemotherapy. Comprehensive analysis uncovered significant differences in enriched pathways, TME, genomic and somatic mutation landscape between the two subgroups. Additionally, integrating the IRGS and TNM stage, a reliable prognostic nomogram was developed to optimize survival prediction, and validated in an independent external dataset for clinical application. Take together, the proposed IRG signature in this study is a promising biomarker for risk stratification and drug efficacy prediction in LUAD patients. This study may be meaningful for explaining the responses of clinical therapeutic drugs and providing new strategies for administrating sufferer of LUAD.