Augmented Parkin-dependent mitophagy underlies the hepatoprotective effect of remote ischemic conditioning used prior to hemorrhagic shock

• Published in: Mitochondrion 2023-05, Vol.70, p.20-30
• Main Authors: Naraiah Mukkala, Avinash, Petrut, Raluca, Goldfarb, Rachel, Leigh Beroncal, Erika, Ho Leung, Chung, Khan, Zahra, Ailenberg, Menachem, Jerkic, Mirjana, Andreazza, Ana C., Rhind, Shawn G., Jeschke, Marc G., Kapus, Andras, Rotstein, Ori D.
• Format: Article
• Language: English
• Subjects: Animals; Hemorrhagic shock-resuscitation; Ischemia; Ischemia–reperfusion injury; Ischemic Preconditioning; Liver Diseases; Mice; Mitochondria; Mitochondrial quality control; Mitophagy; Parkin-dependent mitophagy; Shock, Hemorrhagic; Ubiquitin-Protein Ligases - genetics
• ISSN: 1567-7249; 1872-8278
• DOI: 10.1016/j.mito.2023.03.002

[Display omitted] •Remote ischemic preconditioning (RIPC) protects wild-type mice from hemorrhagic shock/resuscitation-induced (HSR) liver ischemia/reperfusion injury and inflammation.•RIPC loses its hepatoprotective capabilities in parkin knockout mice.•RIPC used prior to HSR causes a parkin-dependent increase in mitophagy. 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.