Particulate matter with aerodynamic diameter not larger than 2.5 μm (PM2.5) escalated the risk of respiratory diseases. Mitochondrial dysfunction may play a pivotal role in PM2.5-induced airway injury. However, the potential effect of PM2.5 on mitochondrial permeability transition pore (mPTP)-related airway injury is still unknown. This study aimed to investigate the role of mPTP in PM2.5-induced mitochondrial dysfunction in airway epithelial cells in vitro. PM2.5 significantly reduced cell viability and caused apoptosis in BEAS-2B cells. We also found PM2.5 caused cellular and mitochondrial morphological alterations, evidenced by the disappearance of mitochondrial cristae, mitochondrial swelling, and the rupture of the outer mitochondrial membrane. PM2.5 induced mPTP opening via upregulation of voltage-dependent anion-selective channel (VDAC), leading to deprivation of mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) generation and intracellular calcium level. PM2.5 suppressed mitochondrial respiratory function by reducing basal and maximal respiration, and ATP production. The mPTP targeting compounds cyclosporin A [CsA; a potent inhibitor of cyclophilin D (CypD)] and VBIT-12 (a selective VDAC1 inhibitor) significantly inhibited PM2.5-induced mPTP opening and apoptosis, and preserved mitochondrial function by restoring mitochondrial membrane potential, reducing mitochondrial ROS generation and intracellular calcium content, and maintaining mitochondrial respiration function. Our data further demonstrated that PM2.5 caused reduction in nuclear expressions of PPARγ and PGC-1α, which were reversed in the presence of CsA. These findings suggest that mPTP might be a potential therapeutic target in the treatment of PM2.5-induced airway injury.
Keywords: Airway epithelial cells; Cyclosporin A; Mitochondrial function; Mitochondrial permeability transition pore; Particulate matter.
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