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亲环素D在衰老细胞的存活中起关键作用。

Cyclophilin D plays a critical role in the survival of senescent cells.

作者信息

Protasoni Margherita, López-Polo Vanessa, Stephan-Otto Attolini Camille, Brandariz Julian, Herranz Nicolas, Mateo Joaquin, Ruiz Sergio, Fernandez-Capetillo Oscar, Kovatcheva Marta, Serrano Manuel

机构信息

Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.

Cambridge Institute of Science, Altos Labs, Granta Park, Cambridge, CB21 6GP, UK.

出版信息

EMBO J. 2024 Dec;43(23):5972-6000. doi: 10.1038/s44318-024-00259-2. Epub 2024 Oct 24.

DOI:10.1038/s44318-024-00259-2
PMID:39448884
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11612481/
Abstract

Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.

摘要

衰老细胞在许多疾病中起致病作用，清除这些细胞是一种很有前景的治疗策略。在此，我们通过全基因组CRISPR/Cas9筛选，鉴定出编码线粒体蛋白亲环蛋白D（CypD）的基因PPIF作为一种新的衰老细胞溶解靶点。亲环蛋白D促进线粒体通透性转换孔（mPTP）的短暂开放，这是一种钙外流的安全机制。我们发现衰老细胞表现出高频的短暂CypD/mPTP开放事件，即“闪烁”。使用包括环孢素A在内的基因或药理学工具抑制CypD，会导致线粒体钙的毒性积累和衰老细胞的死亡。对另一个线粒体钙外流通道NCLX进行基因或药理学抑制，也会导致衰老细胞溶解，而抑制主要的钙内流通道MCU，则可防止由CypD抑制诱导的衰老细胞溶解。我们得出结论，衰老细胞对线粒体钙离子升高高度敏感，短暂的CypD/mPTP开放是衰老细胞存活的关键适应机制。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85b3/11612481/a13668d5c067/44318_2024_259_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85b3/11612481/86c335dbe471/44318_2024_259_Fig8_ESM.jpg
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