Abstract:
:The mitochondrial permeability transition pore (mPTP) plays a critical role in the pathogenesis of cardiovascular diseases, including ischemia/reperfusion injury. Although the pore structure is still unresolved, the mechanism through which cyclophilin D (CypD) regulates mPTP opening is the subject of intensive studies. While post-translational modifications of CypD have been shown to modulate pore opening, specific phosphorylation sites of CypD have not yet been identified. We hypothesized here that phosphorylation of CypD on a serine residue controls mPTP opening and subsequent cell death at reperfusion. We combined in silico analysis with in vitro and genetic manipulations to determine potential CypD phosphorylation sites and their effect on mitochondrial function and cell death. Importantly, we developed an in vivo intramyocardial adenoviral strategy to assess the effect of the CypD phosphorylation event on infarct size. Our results show that although CypD can potentially be phosphorylated at multiple serine residues, only the phosphorylation status at S191 directly impacts the ability of CypD to regulate the mPTP. Protein-protein interaction strategies showed that the interaction between CypD and oligomycin sensitivity-conferring protein (OSCP) was reduced by 45% in the phosphoresistant S191A mutant, whereas it was increased by 48% in the phosphomimetic S191E mutant cells. As a result, the phosphoresistant CypD S191A mutant was protected against 18 h starvation whereas cell death was significantly increased in phosphomimetic S191E group, associated with mitochondrial respiration alteration and ROS production. As in vivo proof of concept, in S191A phosphoresistant rescued CypD-KO mice developed significantly smaller infarct as compared to WT whereas infarct size was drastically increased in S191E phosphomimetic rescued mice. We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Hurst S,Gonnot F,Dia M,Crola Da Silva C,Gomez L,Sheu SSdoi
10.1038/s41419-020-02864-5subject
Has Abstractpub_date
2020-08-19 00:00:00pages
661issue
8issn
2041-4889pii
10.1038/s41419-020-02864-5journal_volume
11pub_type
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journal_title:Cell death & disease
pub_type: 杂志文章
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journal_title:Cell death & disease
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journal_title:Cell death & disease
pub_type: 杂志文章,已发布勘误
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journal_title:Cell death & disease
pub_type: 已发布勘误
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journal_title:Cell death & disease
pub_type: 杂志文章
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journal_title:Cell death & disease
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更新日期:2019-07-11 00:00:00
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journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.527
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journal_title:Cell death & disease
pub_type: 杂志文章
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更新日期:2011-03-10 00:00:00
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journal_title:Cell death & disease
pub_type: 已发布勘误
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更新日期:2019-09-05 00:00:00
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journal_title:Cell death & disease
pub_type: 杂志文章,收录出版
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journal_title:Cell death & disease
pub_type: 杂志文章,评审
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journal_title:Cell death & disease
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journal_title:Cell death & disease
pub_type: 杂志文章
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