| RRC ID |
61946
|
| Author |
Huang C, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA.
|
| Title |
Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1.
|
| Journal |
PLoS One
|
| Abstract |
Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia (sI) in vitro and IPC of hearts to investigate the role of Parkin in mediating cardioprotection ex vivo and in vivo. In HL-1 cells, sI induced Parkin translocation to mitochondria and mitochondrial elimination. IPC induced Parkin translocation to mitochondria in Langendorff-perfused rat hearts and in vivo in mice subjected to regional IPC. Mitochondrial depolarization with an uncoupling agent similarly induced Parkin translocation to mitochondria in cells and Langendorff-perfused rat hearts. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports indicating a role for p62/SQSTM1 in mitophagy, we found that depletion of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to sI. While wild type mice showed p62 translocation to mitochondria and an increase in ubiquitination, Parkin knockout mice exhibited attenuated IPC-induced p62 translocation to the mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.
|
| Volume |
6(6)
|
| Pages |
e20975
|
| Published |
2011-1-1
|
| DOI |
10.1371/journal.pone.0020975
|
| PII |
PONE-D-11-03037
|
| PMID |
21687634
|
| PMC |
PMC3110820
|
| MeSH |
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Autophagy*
Cell Line
Cell Polarity
Heat-Shock Proteins / metabolism*
Ischemic Preconditioning, Myocardial*
Mice
Mitochondria / metabolism*
Mitochondria / pathology*
Myocardial Ischemia / metabolism
Myocardial Ischemia / pathology
Myocardial Ischemia / physiopathology
Myocardium / metabolism
Myocardium / pathology
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology
Protein Transport
Reperfusion Injury / prevention & control
Sequestosome-1 Protein
Stress, Physiological
Ubiquitin-Protein Ligases / metabolism*
|
| IF |
2.74
|
| Resource |
| Human and Animal Cells |
Atg5^(+/+)MEF(RCB2710)
Atg5^(-/-)MEF(RCB2711) |
