Involvement of NEAT1/PINK1-mediated mitophagy in chronic obstructive pulmonary disease induced by cigarette smoke or PM2.5

Abstract

Background: This study sought to explore the underlying mechanism of long non-coding ribonucleic acid nuclear enriched abundant transcript 1 (NEAT1) and PTEN-induced kinase 1 (PINK1)-mediated mitophagy in chronic obstructive pulmonary disease (COPD) induced by cigarette smoke (CS) or fine particular matter (PM 2.5 ). Methods:In total, 30 male Wistar Rats were divided into the following 3 groups: (I) the COPD group exposed to CS (CSM); (II) the COPD group exposed to PM 2.5 (PMM); and (III) the control (Ctrl) group.Pulmonary function, the enzyme-linked immunoassay analysis results, the histopathology results, and the ultrastructures of the lung tissues were examined in the 3 groups, and NEAT1 expression levels and the mitophagy-related protein PINK1, Parkin, LC3B, and p62 levels were assessed by quantitative reverse transcription PCR (RT-qPCR) and Western blotting. The A549 cells were transfected with small interfering ribonucleic acid (siRNA) targeting NEAT1, and subsequently stimulated with CS extract (CSE) and PM 2.5 suspension (PMS). Mitochondrial dysfunction and enhanced mitophagy were observed, and the expression of the NEAT1/PINK1 pathway was assessed by RT-qPCR and Western blotting. Results: Both the CSM and PMM groups had a lower tidal volume (V T ), minute ventilation (MV), and a higher respiratory rate (f) than the Ctrl group. The interleukin (IL)-6, IL-8, and tumor necrosis factoralpha levels in the serum and bronchoalveolar lavage fluid of the CSM and PMM groups were significantly increased. The histological examination results revealed airway remodeling, the formation of pulmonary bullae, and emphysema in the CSM and PMM groups. Subsequently, the ultrastructures of the lung tissues in the CSM and PMM groups showed mitochondrial swelling and autophagosomes. Additionally, NEAT1 expression, the level of the mitophagy-related protein PINK1, Parkin, and the ratio of LC3-II/I increased synchronously. Further, NEAT1 siRNA blocked PINK1 expression, inhibited mitochondrial dysfunctions, and mitophagy activation in the A549 cells exposed to CSE or PMS. Conclusions: Our results suggest that CS and PM 2.5 exposure induce mitochondrial dysfunction, and the NEAT1/PINK1 pathway plays a critical role in the occurrence and development of COPD by regulating mitophagy.

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

“…This is supported by our data. Our pathway analysis also corroborates prior literature on the possible role of mitochondrial autophagy (mitophagy) in emphysema (65, 66). The canonical WNT signaling pathway, which maintains tissue homeostasis and regulates cell differentiation and apoptosis (67), is a known activator of mitochondrial biogenesis (68).…”

The utility of long non-coding RNAs in chronic obstructive pulmonary disease: a comprehensive analysis

“…Hence, we advise that up-regulated lncRNAs should be a better choice for diagnosis accuracy. NEAT1 is a lncRNA found to be expressed widely in a variety of mammalian cell types and involved in the occurrence and development of a variety of diseases [ 47 , 48 ]. Ming et al found high expression of NEAT1 in AECOPD and COPD patients; the increased expression of NEAT1 may be associated with the stage of COPD and positively correlated with GOLD grade [ 13 , 15 ], and the underlining mechanisms were considered to regulate inflammation.…”

Codium fragile Suppressed Chronic PM2.5-Exposed Pulmonary Dysfunction via TLR/TGF-β Pathway in BALB/c Mice

“…Repeated and chronic exposure to PM 2.5 causes reduced mitochondrial fusion and impaired dynamics with the reduction of optic atrophy 1 (OPA1) and mitofusin2 (MFN2) PM 2.5 causes mitochondrial morphology damage with mitochondrial swelling, vacuole formation, and crystal destruction [27]. In addition, in damaged mitochondria, PTEN-induced kinase 1 (PINK1), a mitophagy regulatory protein, accumulates in the mitochondrial outer membrane, thereby inducing an abnormal mitophagy process resulting in a decrease in mitochondrial volume, inhibition of mitochondrial respiratory function, and an increase in mitochondrial ROS levels [28]. This mitochondrial deficit induces abnormal energy metabolism in lung tissues by reducing the MMP level and damaging the sodium-potassium pump and calcium pump [26].…”