PINK1 overexpression protects against cerebral ischemia through Parkin regulation

Abstract

Mitochondrial dynamics and function are important for cell survival regulation under stress. In this study, we report that cerebral ischemia/reperfusion (I/R) injury significantly reduced mitochondrial function through reduced PTEN‐induced kinase 1 (PINK1) expression, ATP (Adenosine triphosphate) levels, and increased oxidative stress compared to sham rats. PINK1 overexpression mice significantly improved mitochondrial function by increased mitochondrial complex I, II, and III activities and ATP levels with concomitant decline in reactive oxygen species levels. PINK1 overexpression mice after I/R injury significantly reduced apoptosis through downregulation of cytochrome c, p53 expressions compared to cerebral I/R injury rats. Furthermore, we showed from parkin siRNA studies that PINK1 regulated phosphorylation parkin is critical to the protection against cerebral I/R injury. Altogether, we show that PINK1 mediated parkin regulation is key to the protection against cerebral I/R injury through regulation of mitochondrial function and apoptosis.

Berberine Promotes Cardiac Function by Upregulating PINK1/Parkin-Mediated Mitophagy in Heart Failure

“…The mechanism(s) involved in mitophagy regulation include PINK1/Parkin-and mitophagy receptors-dependent pathway (Eiyama and Okamoto, 2015). The study showed that PINK1/Parkin acts cooperatively in adjusting mitochondrial balancing function and marking impaired mitochondria (Fan et al, 2019;Wen et al, 2020). Notably, ubiquitylation and deubiquitylation play roles in modulating significantly (Tanaka, 2020).…”

Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats

“…PINK1 and Parkin are two proteins stably expressed in the nervous system of human being [ 39 , 40 ], and crucial for neuronal survival functioning as multipurpose proteins in a variety of toxic insults [ 41 , 42 ]. Notably, PINK1/Parkin pathway has been arisen extensive attention in exploring the interplay between hypoxia-related mitophagy and cerebral ischemia [ 8 , 19 , 22 ]. As a sensor of mitochondrial damage, PINK1 accumulates in the OMM and recruits cytosolic Parkin to damaged mitochondria.…”

“…Then Parkin stimulates the degradation of mitochondria by ubiquitination of mitochondrial proteins [ 43 ]. Cerebral ischemia would alter PINK1 and Parkin expression [ 19 , 22 ]. Demyanenko et al demonstrated that expression of Parkin and PINK1 were increased in the cortical penumbra at 1 h after photothrombotic infarction in Wistar rats [ 44 ].…”

“…However, HPC-promoted PINK1 and Parkin translocation to mitochondria, accompanied by the increased mitochondrial ubiquitination and subsequent mitochondrial clearance after tGCI. Moreover, PINK1/Parkin-induced mitophagy is protective for the hippocampus in vivo and in vitro against cerebral ischemia [ 20 , 21 ], which mainly arises from the suppression of oxidative stress, alleviation of neuronal apoptosis [ 48 ], and improvement of mitochondrial function [ 22 ]. Consistently, we found that PINK1 silencing abrogated the activation of PINK1/Parkin pathway, inhibited the degradation of damaged mitochondria, and finally eliminated the neuroprotection induced by HPC after tGCI.…”

“…Wang et al demonstrated that the activation of PINK1/Parkin pathway effectively ameliorates neuronal damage in the cortex and hippocampal CA1 region via mediating damaged mitochondrial clearance after MCAO [ 21 ]. Furthermore, PINK1/Parkin pathway plays a vital role in the interplay between hypoxia-related mitophagy and cerebral ischemia [ 19 , 22 ]. Nevertheless, little is understood whether HPC promotes mitochondrial ubiquitination via activating PINK1/Parkin pathway, thus inducing mitophagy to attenuate neuronal injury after tGCI.…”