BI1 alleviates cardiac microvascular ischemia‐reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F‐actin pathways

Abstract

Pathogenesis of cardiac microvascular ischemia-reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator of mitochondrial fission remains obscure. Bax inhibitor 1 (BI1) is linked to multiple mitochondrial functions, and there have been no studies investigating the contribution of BI1 on mitochondrial fission in the setting of cardiac microvascular IR injury. This study was undertaken to establish the action of BI1 on the cardiac microvascular reperfusion injury and figure out whether BI1 sustained endothelial viability via inhibiting mitochondrial fission. Our observation indicated that BI1 was downregulated in reperfused hearts and overexpression of BI1 attenuated microvascular IR injury. Mechanistically, reperfusion injury elevated the levels of xanthine oxidase (XO), an effect that was followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F-actin depolymerization and the latter promoted mitochondrial fission. Aberrant fission caused mitochondrial dysfunction and ultimately activated mitochondrial apoptosis in cardiac microvascular endothelial cells. By comparison, BI1 overexpression repressed XO expression and thus neutralized ROS, interrupting F-actin-mediated mitochondrial fission. The inhibitory effect of BI1 on mitochondrial fission sustained endothelial viability, reversed endothelial barrier integrity, attenuated the microvascular inflammation response, and maintained microcirculation patency. Altogether, we conclude that BI1 is essential in maintaining mitochondrial homeostasis and alleviating cardiac microvascular IR injury. Deregulated BI1 via the XO/ROS/F-actin pathways plays a causative role in the development of cardiac microvascular reperfusion injury.

Renalase Attenuates Mouse Fatty Liver Ischemia/Reperfusion Injury through Mitigating Oxidative Stress and Mitochondrial Damage via Activating SIRT1

“…In line with this finding, mitochondrial fission also plays a vital role in mediating cell death under IR injury [27]. Previous studies have shown that mitochondrial fission and fragmentation were markedly promoted in an IR-or H 2 O 2 -induced oxidative stress model and repressed mitochondrial fission through inhibiting Drp1 activity-attenuated IR-induced cell death [27,28,[58][59][60]. Consistent with previous findings, our results showed that t-BHP-induced oxidative stress promoted mitochondria fission and cell apoptosis.…”

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…NR4A1 induces Mff phosphorylation and enhances Drp1 recruitment onto mitochondria [135], leading to mitochondrial fragmentation. In contrast, BI-1 interrupts the ROS-mediated mitochondrial damage and partly blocks mitochondrial fission-induced endothelial cell death [131,136]. However, the relationship between mitochondrial fission and oxidative stress and the threshold of physiological mitosis shift to fatal mitochondrial fission require further investigation.…”

“…Once positioned on the outer mitochondrial membrane, Drp1 interacts with four mitochondrial-bound proteins that serve as Drp1 receptors (mitochondrial dynamic proteins of 49 and 51 kDa (Mid49 and Mid51), mitochondrial fission protein 1 (Fis1), and mitochondrial fission factor (Mff), where it constricts and cleaves the mitochondria [122] (Figure 2). (NR4A1) [135] or Bax inhibitor-1 (BI-1) [131,136], respectively. NR4A1 induces Mff phosphorylation and enhances Drp1 recruitment onto mitochondria [135], leading to mitochondrial fragmentation.…”

“…Although the role of mitochondrial fission in cardiomyocyte I/R injury has been widely explored [128][129][130], the regulatory mechanisms and functional contributions of fission in endothelial I/R injury remain unclear. Based on recent studies [127,[131][132][133][134][135][136], mitochondrial fission affects endothelial cell fate possibly through three mechanisms. First, excessive mitochondrial fission causes mitochondrial DNA damage, as evidenced by mitochondrial DNA double strand breakage.…”

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

“…ER also exerts a critical effect on protein generation, synthesis, modification and transport [11][12][13]. The primary result of ER dysfunction is ER stress, an effect that is accompanied with an accumulation of misfolded proteins and calcium overloading [14,15]. Subsequently, disruption of calcium homeostasis has been found to be associated with oxidative stress that contributes to the activation of apoptosis in a mechanism through ER stress [3,16].…”