Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome

Abstract

Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin−/− mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

“…Additionally, the findings indicate that Parkin is involved in the mechanism underlying PD-mediated mitophagy. These findings are in agreement with those of our previous study, in which we reported that PD activates Parkin-mediated mitophagy in acute lung injury [18].…”

“…Our previous study demonstrated that polydatin (PD) attenuates MD and inflammation in a rat model of SI-AKI [1], but the underlying pathways were not investigated. We have also demonstrated in a previous study that PD mediates Parkin-dependent mitophagy and protects against acute respiratory distress syndrome [18]. Based on our previous findings and those of other studies, in the present study, we hypothesized that Parkinmediated mitophagy plays a role in the protective effects of PD against MD and NLRP3 activation in SI-AKI and established a mouse model of sepsis.…”

“…Therefore, in the present study, we investigated the role of mitophagy in the protective effects of PD against SI-AKI. For this purpose, we treated SI-AKI model mice with mdivi-1, an inhibitor of mitophagy [18], and studied the effects of PD in Parkinknockout mice. The results showed that inhibition of mitophagy blocked the protective effect of PD against SI-AKI, renal dysfunction, and the upregulated expression of KIM-1 and serum cytokines, including TNF-α, IL-1β, and IL-6.…”

“…After the procedure, the mice were not fed, but they were given free access to water. Immediately after the CLP procedure, the mice were administered 30 mg/kg PD (or mitochondrial division inhibitor [mdivi-1], 3 mg/kg) and EX527 (10 mg/g) via tail vein injection, based on our previous findings [1,18,20], and they were sacrificed at 12 h after CLP. In the present study, 6 mice were included in each group.…”

“…Mitophagy was inhibited in SI-AKI model mice by knockout of Parkin or treatment with mdivi-1 (a widely used inhibitor of mitophagy) [18]. The mice were administered vehicle, PD (30 mg/kg), or PD along with mdivi-1 (3 mg/kg).…”