Impairment of Mitochondrial ATP Synthesis Induces RIPK3-dependent Necroptosis in Lung Epithelial Cells During Lung Injury by Lung Inflammation

Abstract

Dysfunction of mitochondrial metabolism is implicated in cellular injury and cell death. While mitochondrial dysfunction is associated with lung injury by lung inflammation, the mechanism by which the impairment of mitochondrial ATP synthesis regulates necroptosis during acute lung injury (ALI) by lung inflammation is unclear. Here, we showed that the impairment of mitochondrial ATP synthesis induces receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis during lung injury by lung inflammation. We found that the impairment of mitochondrial ATP synthesis by oligomycin, an inhibitor of ATP synthase, resulted in increased lung injury and RIPK3 levels in lung tissues during lung inflammation by LPS in mice. The elevated RIPK3 and RIPK3 phosphorylation levels by oligomycin resulted in high mixed lineage kinase domain-like (MLKL) phosphorylation, the terminal molecule in necroptotic cell death pathway, in lung epithelial cells during lung inflammation. Moreover, the levels of protein in bronchoalveolar lavage fluid (BALF) were increased by the activation of necroptosis via oligomycin during lung inflammation. Furthermore, the levels of ATP5A, a catalytic subunit of the mitochondrial ATP synthase complex for ATP synthesis, were reduced in lung epithelial cells of lung tissues from patients with acute respiratory distress syndrome (ARDS), the most severe form of ALI. The levels of RIPK3, RIPK3 phosphorylation and MLKL phosphorylation were elevated in lung epithelial cells in patients with ARDS. Our results suggest that the impairment of mitochondrial ATP synthesis induces RIPK3-dependent necroptosis in lung epithelial cells during lung injury by lung inflammation.

A bibliometric analysis of programmed cell death in acute lung injury/acute respiratory distress syndrome from 2000 to 2022

“…However, the regulatory pathway of necroptosis in the pathophysiological mechanism of ALI has not been elucidated. Researchers specifically focused on the life and death of mitochondria and the role of inflammatory factors represented by tumor necrosis factor in the pathophysiological mechanism of ALI/ARDS [ [50] , [51] , [52] ]. Pyroptosis is a new way of cell death in recent years.…”

Some Macrophages With High Expression of CHOP Undergo Necroptosis in Chronic Rhinosinusitis

“…It was found that both RIPK3 and MLKL expressions were elevated in LPS-induced lung injury mouse models. 22,23 Geng et al 24 found that LPS could activate RIPK3/MLKL-mediated necroptosis in oral epithelial cells. However, in our study, LPS did not induce necroptosis of nasal polyps, which may be due to the interaction of multiple cells.…”

Cell type‐specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases

“…Aberrant mitochondrial metabolism mediates cell damage and death 76 . Inhibition of mitochondrial ATP synthesis via oligomycin triggers RIPK3‐based necroptotic signaling in pulmonary epithelial cells in the settings of LPS‐induced ALI 77 . L‐OPA1 is an important mitochondrial inner membrane fusion protein, and the loss can impair mitochondrial functions 78,79 .…”

“…76 Inhibition of mitochondrial ATP synthesis via oligomycin triggers RIPK3-based necroptotic signaling in pulmonary epithelial cells in the settings of LPS-induced ALI. 77 L-OPA1 is an important mitochondrial inner membrane fusion protein, and the loss can impair mitochondrial functions. 78,79 L-OPA1 is downregulated in alveolar epithelial cells upon LPS challenge.…”