PINK1 Activation and Translocation to Mitochondria-Associated Membranes Mediates Mitophagy and Protects Against Hepatic Ischemia/Reperfusion Injury

Abstract

Hepatic ischemia/reperfusion (I/R) injury is a major concern in liver surgery settings. Mitochondria are critical targets or the origin of tissue injury, particularly I/R injury. Mitophagy, a selective form of autophagy, is a fundamental process that removes damaged or unwanted mitochondria for mitochondrial quality control, but its role in hepatic I/R remains unclear. In the present study, we investigated the role of mitophagy in hepatic I/R by focusing on PTEN-induced putative kinase 1 (PINK1). Livers from 10-week-old mice and primary hepatocytes were subjected to in vivo hepatic I/R and in vitro hypoxia-reoxygenation (H/R), respectively. Analyses of oxidative stress, immunoblotting, and ATP generation showed that hepatic I/R leads to mitochondrial damage. Dysfunctional mitochondria promoted reactive oxygen species (ROS) production and apoptosis. Hepatic I/R led to decreases in the mitochondrial proteins COX4 and TOM20 and mitochondrial DNA and increases in the autophagy-related indicators LC3 and P62, which indicates that hepatic I/R promotes mitophagy. We found that I/R also leads to endoplasmic reticulum stress, which has frequent signal communication with mitochondria through the mitochondria-associated membranes (MAMs). We showed that the mitophagy-related proteins Parkin, Beclin, optineurin were enhanced in hepatic I/R. No significant change is in PINK1 but it translocated to MAMs region to initiate mitophagy. The silencing PINK1 by shRNA in cultured primary hepatocytes reduced the level of H/R-induced mitophagy, leading to the accumulation of dysfunctional mitochondria during H/R, increased production of ROS, mitochondria-induced apoptosis, and eventually hepatocyte death. Taken together, these findings indicate that PINK1-mediated mitophagy plays a key role in mitochondrial quality control and liver cell survival during I/R.

Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury

“…Autophagy is a cellular process beneficial to cellular survival and homeostasis, and numerous investigations have provided evidence that hepatic autophagy, especially mitophagy, is cytoprotective against I/R injury. 7,21 By selectively removing dysfunctional or damaged mitochondria, mitophagy preserves mitochondrial morphology and function. We recently reported that ALR-enhanced mitophagy in ethanol-damaged hepatocytes.…”

<p><em>PINK1</em> Overexpression Promotes Cell Migration and Proliferation via Regulation of Autophagy and Predicts a Poor Prognosis in Lung Cancer Cases</p>

“…In this context, the unhydrolyzed PINK1 protein attaches to the outer mitochondrial membrane and activates the autophagy process to eliminate the dysfunctional mitochondria. [36][37][38] Autophagy is also associated with cell migration, proliferation, and apoptosis, although the molecular mechanisms underlying the relationship between autophagy and cellular activities remain unclear. [39][40][41] The present study revealed that autophagy was severely suppressed in cells with stable interference of PINK1 expression ( Figure 4B-E), which suggests that deficient autophagy might be related to the PINK1 mediation of suppression of cell proliferation and migration.…”

Hepatic 31P‐magnetic resonance spectroscopy identified the impact of melatonin‐pretreated mitochondria in acute liver ischaemia‐reperfusion injury

“…17,18 However, severely impaired mitochondrial function and activity have clearly identified in setting of liver ischaemia-reperfusion 4,19,20 with subsequent alternation in energy metabolism, generation of reactive oxygen species (ROS), inflammatory cell infiltration and cellular apoptosis [21][22][23][24] and ultimately irreversible damages to mitochondria, 16,25 exhausting ATP in ischaemia-reperfusion liver. 4,16,21,[25][26][27] These findings 4,16,[19][20][21][22][23][24][25][26][27] highlight that the quantity (ie amount) and quality (functional integrity) of mitochondria play extremely important roles on acute liver IRI. Accordingly, these aforementioned issues 4,16,21,[25][26][27] raise the hypothesis that restoration of mitochondrial function through exogenous mitochondrial transfusion may be a potential strategy for the treatment of acute hepatic IRI.…”

“…4,16,21,[25][26][27] These findings 4,16,[19][20][21][22][23][24][25][26][27] highlight that the quantity (ie amount) and quality (functional integrity) of mitochondria play extremely important roles on acute liver IRI. Accordingly, these aforementioned issues 4,16,21,[25][26][27] raise the hypothesis that restoration of mitochondrial function through exogenous mitochondrial transfusion may be a potential strategy for the treatment of acute hepatic IRI.…”