Abstract
Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.
Highlights
Transient global cerebral ischemia, which is common in clinical conditions such as drowning, cardiac arrest, and cardiopulmonary bypass surgery, leads to selective neuronal death in the hippocampal CA1 layer [1]
hypoxic postconditioning (HPC) activates mitophagy and alleviates neuronal death in hippocampal CA1 after Transient global cerebral ischemia (tGCI) First, mitophagy was examined by transmission electron microscopy (TEM)
Relative to Sham rats, the cytoplasmic volume fractions of mitophagosomes increased after tGCI with or without HPC, which further increased in HPC group at 50 h of reperfusion (Fig. 1B)
Summary
Transient global cerebral ischemia (tGCI), which is common in clinical conditions such as drowning, cardiac arrest, and cardiopulmonary bypass surgery, leads to selective neuronal death in the hippocampal CA1 layer [1]. Perpetuated mitochondrial impairment is a common consequence of cerebral ischemic insult progression, leading to the opening of mitochondrial membrane transition pore, the elevation of oxidative stress, and the induction of apoptosis [3]. Well-studied selective autophagy, plays an essential role in protecting neurons against cerebral ischemia/reperfusion injury by selectively removing impaired or dysfunctional mitochondria [4, 5]. Mitophagy-related mitochondrial clearance in the reperfusion phase was beneficial to ischemia/reperfusioninduced neuronal injury in C57BL/6 mice after transient middle cerebral artery occlusion (MCAO) and in cultured cortical neurons with oxygen-glucose deprivation-reperfusion [8]. Mdivi-1, a mitophagy inhibitor, abolished the reduction of mitochondrial markers translocase of outer mitochondrial membrane 20 homolog (TOMM20) and cytochrome c oxidase subunit 4 isoform 1, increased infarct volumes and enhanced neurological
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