Oxidative Biomarkers Associated with the Pulmonary Manifestation of Post-COVID-19 Complications.

INTRODUCTION: The role of mitochondria in post coronavirus disease 2019 (post-COVID-19) complications is unclear, especially in the long-term pulmonary complications. This study aims to investigate the association between post-COVID-19 pulmonary complications and mitochondrial regulatory proteins in the context of oxidative stress. METHODOLOGY: Patients who had recovered from COVID-19 were enrolled. According to the evidence of persistent interstitial lung lesions on computed tomography (CT), patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(-)). We randomly selected 80 patients for investigation (40 subjects for each group). Biomarkers levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The serum concentrations of mitochondrial regulatory proteins were significantly higher in the P(+) group, including PTEN-induced kinase 1 (PINK1): 1.62 [1.02-2.29] ng/mL vs. 1.34 [0.94-1.74] ng/mL (p = 0.046); Dynamin-1-like protein (DNM1L): 1.6 [0.9-2.4] ng/mL IQR vs. 0.9 [0.5-1.6] ng/mL (p = 0.004); and Mitofusin-2 (MFN2): 0.3 [0.2-0.5] ng/mL vs. 0.2 [0.1-0.3] ng/mL IQR (p = 0.001). Patients from the P(+) group also had higher serum levels of chemokine ligand 18 (PARC, CCL18), IL-6, and tumour necrosis factor-alpha (TNF-α) cytokines than the P(-) group. The concentration of interferon alpha (IFN-α) was decreased in the P(+) group. Furthermore, we observed statistically significant correlations between the advanced glycation end product (sRAGE) and TNF-α (Pearson's factor R = 0.637; p < 0.001) and between serum levels of DNM1L and IFN-α (Pearson's factor R = 0.501; p = 0.002) in P(+) patients. CONCLUSIONS: Elevated concentrations of mitochondrial biomarkers in post-COVID-19 patients with long-term pulmonary complications indicate their possible role in the pathobiology of COVID-19 pulmonary sequelae. Oxidative stress is associated with the immune response and inflammation after COVID-19. TNF-α could be a promising biomarker for predicting pulmonary complications and may be a potential target for therapeutic intervention in patients with post-COVID-19 complications.

The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a condition which affects mainly older adults, that suggests mitochondrial dysfunction and oxidative stress, which follow cells senescence, and might contribute to the disease onset. We have assumed pathogenesis associated with crosstalk between the extracellular matrix (ECM) and mitochondria, mainly based on mitochondrial equilibrium impairment consisting of (1) tyrosine kinases and serine-threonine kinase (TKs and ST-Ks) activation via cytokines, (2) mitochondrial electron transport chain dysfunction and in consequence electrons leak with lower ATP synthesis, (3) the activation of latent TGF-ß via αVß6 integrin, (4) tensions transduction via α2ß1 integrin, (5) inefficient mitophagy, and (6) stress inhibited biogenesis. Mitochondria dysfunction influences ECM composition and vice versa. Damaged mitochondria release mitochondrial reactive oxygen species (mtROS) and the mitochondrial DNA (mtDNA) to the microenvironment. Therefore, airway epithelial cells (AECs) undergo transition and secrete cytokines. Described factors initiate an inflammatory process with immunological enhancement. In consequence, local fibroblasts exposed to harmful conditions transform into myofibroblasts, produce ECM, and induce progression of fibrosis. In our review, we summarize numerous aspects of mitochondrial pathobiology, which seem to be involved in the pathogenesis of lung fibrosis. In addition, an increasing body of evidence suggests considering crosstalk between the ECM and mitochondria in this context. Moreover, mitochondria and ECM seem to be important players in the antifibrotic treatment of IPF.

The ILK-MMP9-MRTF axis is crucial for EndMT differentiation of endothelial cells in a tumor microenvironment.

Increasing evidence indicates that the tumor microenvironment is a critical factor supporting cancer progression, chemoresistance and metastasis. Recently, cancer-associated fibroblasts (CAFs) have been recognized as a crucial tumor stromal component promoting cancer growth and invasiveness via modulation of the extracellular matrix (ECM) structure, tumor metabolism and immune reprogramming. One of the main sources of CAFs are endothelial cells undergoing the endothelial-mesenchymal transition (EndMT). EndMT is mainly promoted by the Transforming Growth Factor-ß (TGF-ß) family secreted by tumor cells, though the role of particular members in EndMT regulation remains poorly understood. Our findings demonstrate that TGF-ß2 induces mesenchymal transdifferentiation of human microvascular endothelial cells (HMEC-1 cells) to CAF-like cells in association with elongated cell morphology, modulation of stress fiber organization, higher α-SMA protein levels and activation of RhoA and Rac-1 pathways. Such regulation is similar to that observed in cells maintained using conditioned medium from invasive colorectal cancer cell line culture. Furthermore, TGF-ß2 stimulation resulted in myocardin-related transcription factor (MRTF) activation and upregulation. Our results demonstrate for the first time that such interaction is sufficient for integrin-linked kinase (ILK) overexpression. ILK upregulation also enhanced MRTF activation via RhoA and Rac-1-MMP9 via inside-out integrin activation. Herein, we propose a new ILK-MMP9-MRTF axis that appears to be critical for EndMT differentiation of endothelial to CAF-like cells. Thus, it might be an attractive target for cancer treatment.