Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada.
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada.
Mitochondrion. 2023 May;70:20-30. doi: 10.1016/j.mito.2023.03.002. Epub 2023 Mar 10.
Hemorrhagic shock-resuscitation (HSR) following trauma contributes to organ dysfunction by causing ischemia-reperfusion injury (IRI). We previously showed that 'remote ischemic preconditioning' (RIPC) exerted multi-organ protection from IRI. Maintenance of mitochondrial quality by clearance of dysfunctional mitochondria via mitophagy is vital in restoring organ integrity. We hypothesized that parkin-dependent mitophagy played a role in RIPC-induced hepatoprotection following HSR.
The hepatoprotective effect of RIPC in a murine model of HSR-IRI was investigated in wild type and parkin-/- animals. Mice were subjected to HSR ± RIPC and blood and organs were collected, followed by cytokine ELISAs, histology, qPCR, Western blots, and transmission electron microscopy.
HSR increased hepatocellular injury, as measured by plasma ALT and liver necrosis, while antecedent RIPC prevented this injury; in parkin mice, RIPC failed to exert hepatoprotection. The ability of RIPC to lessen HSR-induced rises in plasma IL-6 and TNFα, was lost in parkin mice. While RIPC alone did not induce mitophagy, the application of RIPC prior to HSR caused a synergistic increase in mitophagy, this increase was not observed in parkin mice. RIPC induced shifts in mitochondrial morphology favoring mitophagy in WT but not in parkin animals.
RIPC was hepatoprotective in WT mice following HSR but not in parkin mice. Loss of protection in parkin mice corresponded with the failure of RIPC plus HSR to upregulate the mitophagic process. Improving mitochondrial quality by modulating mitophagy, may prove to be an attractive therapeutic target in disease processes caused by IRI.
创伤后发生的失血性休克复苏（HSR）会导致缺血再灌注损伤（IRI），从而导致器官功能障碍。我们之前的研究表明，“远程缺血预处理”（RIPC）可对 IRI 引起的多器官损伤发挥保护作用。通过自噬清除功能失调的线粒体来维持线粒体质量对于恢复器官完整性至关重要。我们假设 parkin 依赖性自噬在 RIPC 诱导的 HSR 后肝保护中发挥作用。
在 HSR-IRI 的小鼠模型中，研究了 RIPC 的肝保护作用，该模型在野生型和 parkin-/-动物中进行。将小鼠进行 HSR ± RIPC 处理，采集血液和器官，随后进行细胞因子 ELISA、组织学、qPCR、Western blot 和透射电镜检查。
HSR 增加了肝细胞损伤，如血浆 ALT 和肝坏死所测，而先前的 RIPC 可预防这种损伤；在 parkin 小鼠中，RIPC 未能发挥肝保护作用。RIPC 降低 HSR 诱导的血浆 IL-6 和 TNFα 升高的能力在 parkin 小鼠中丧失。虽然 RIPC 本身不能诱导自噬，但在 HSR 之前应用 RIPC 会引起自噬的协同增加，在 parkin 小鼠中未观察到这种增加。RIPC 诱导线粒体形态发生变化，有利于 WT 中的自噬，但不利于 parkin 动物中的自噬。
在 HSR 后，RIPC 在 WT 小鼠中具有肝保护作用，但在 parkin 小鼠中没有。在 parkin 小鼠中保护作用的丧失与 RIPC 加 HSR 未能上调自噬过程相对应。通过调节自噬来改善线粒体质量，可能成为由 IRI 引起的疾病过程中的一个有吸引力的治疗靶点。
