PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation.

Contrast-induced acute kidney injury (CI-AKI) occurs in more than 30% of patients after intravenous iodinated contrast media and causes serious complications, including renal failure and mortality. Recent research has demonstrated that routine antioxidant and alkaline therapy failed to show benefits in CI-AKI patients with high risk for renal complications. Mitophagy is a mechanism of selective autophagy, which controls mitochondrial quality and mitochondrial reactive oxygen species (ROS) through degradation of damaged mitochondria. The role of mitophagy and its regulation of apoptosis in CI-AKI are poorly understood. In this study, we demonstrated that mitophagy was induced in renal tubular epithelial cells (RTECs) during CI-AKI, both in vivo and in vitro. Meanwhile, contrast media-induced mitophagy was abolished when silencing PINK1 or PARK2 (Parkin), indicating a dominant role of the PINK1-Parkin pathway in mitophagy. Moreover, mitochondrial damage, mitochondrial ROS, RTEC apoptosis, and renal injury under contrast exposure were more severe in PINK1- or PARK2-deficient cells and mice than in wild-type groups. Functionally, PINK1-Parkin-mediated mitophagy prevented RTEC apoptosis and tissue damage in CI-AKI through reducing mitochondrial ROS and subsequent NLRP3 inflammasome activation. These results demonstrated that PINK1-Parkin-mediated mitophagy played a protective role in CI-AKI by reducing NLRP3 inflammasome activation.

Lin Q ，Li S ，Jiang N ，Shao X ，Zhang M ，Jin H ，Zhang Z ，Shen J ，Zhou Y ，Zhou W ，Gu L ，Lu R ，Ni Z ... -  《Redox Biology》

Augmenter of liver regeneration reduces mitochondria-derived ROS and NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy in ischemia-reperfusion-induced renal tubular injury.

Ischemia-reperfusion (IR) injury is one of the main causes of acute kidney disease (AKI). Several studies have shown that mitochondrial damage, which leads to increased production of reactive oxygen species (ROS), plays a vital role in the pathogenesis of IR-induced AKI. Increased ROS production can cause oxidative damage and activate the inflammasome in renal tubular cells, ultimately resulting in apoptosis or necrosis. Mitophagy is a type of selective autophagy that plays a protective role in AKI by regulating the quality of mitochondria and reducing the production of ROS. We previously reported that the augmenter of liver regeneration (ALR) exhibits antiapoptotic and antioxidant functions, although the precise mechanisms of action need to be studied further. In the current study, ALR was overexpressed and an in vitro model of IR injury was constructed. The overexpression of ALR reduced the production of mitochondria-derived ROS (mtROS), the activation of the NLRP3 inflammasome, and the rate of apoptosis. Moreover, this suppression of mtROS production and inflammasome activation was mediated through the PTEN-induced kinase 1 (PINK1)/Parkin pathway of mitophagy. These results suggest that ALR can alleviate IR-induced apoptosis via the PINK1/Parkin mitophagy pathway to reduce the production of mtROS and limit the activation of the NLRP3 inflammasome.

Zhu D ，Zhong J ，Gong X ，Wu X ... -  《-》

Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy.

Lin Q ，Li S ，Jiang N ，Jin H ，Shao X ，Zhu X ，Wu J ，Zhang M ，Zhang Z ，Shen J ，Zhou W ，Gu L ，Lu R ，Ni Z ... -  《-》

PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury.

Wang Y ，Tang C ，Cai J ，Chen G ，Zhang D ，Zhang Z ，Dong Z ... -  《Cell Death & Disease》

NLRP3 Deficiency Protects Against Intermittent Hypoxia-Induced Neuroinflammation and Mitochondrial ROS by Promoting the PINK1-Parkin Pathway of Mitophagy in a Murine Model of Sleep Apnea.

Obstructive sleep apnea (OSA) associated neurocognitive impairment is mainly caused by chronic intermittent hypoxia (CIH)-triggered neuroinflammation and oxidative stress. Previous study has demonstrated that mitochondrial reactive oxygen species (mtROS) was pivotal for hypoxia-related tissue injury. As a cytosolic multiprotein complex that participates in various inflammatory and neurodegenerative diseases, NLRP3 inflammasome could be activated by mtROS and thereby affected by the mitochondria-selective autophagy. However, the role of NLRP3 and possible mitophagy mechanism in CIH-elicited neuroinflammation remain to be elucidated. Compared with wild-type mice, NLRP3 deficiency protected them from CIH-induced neuronal damage, as indicated by the restoration of fear-conditioning test results and amelioration of neuron apoptosis. In addition, NLRP3 knockout mice displayed the mitigated microglia activation that elicited by CIH, concomitantly with elimination of damaged mitochondria and reduction of oxidative stress levels (malondialdehyde and superoxide dismutase). Elevated LC3 and beclin1 expressions were remarkably observed in CIH group. In vitro experiments, intermittent hypoxia (IH) significantly facilitated mitophagy induction and NLRP3 inflammasome activation in microglial (BV2) cells. Moreover, IH enhanced the accumulation of damaged mitochondria, increased mitochondrial depolarization and augmented mtROS release. Consistently, NLRP3 deletion elicited a protective phenotype against IH through enhancement of Parkin-mediated mitophagy. Furthermore, Parkin deletion or pretreated with 3MA (autophagy inhibitor) exacerbated these detrimental actions of IH, which was accompanied with NLRP3 inflammasome activation. These results revealed NLRP3 deficiency acted as a protective promotor through enhancing Parkin-depended mitophagy in CIH-induced neuroinflammation. Thus, NLRP3 gene knockout or pharmacological blockage could be as a potential therapeutic strategy for OSA-associated neurocognitive impairment.

Wu X ，Gong L ，Xie L ，Gu W ，Wang X ，Liu Z ，Li S ... -  《Frontiers in Immunology》