Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3 (Publication with Expression of Concern. See vol. 129, pg. 869, 2016) (Retracted article. See vol. 129, pg. 2685, 2016)
Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3 (Publication with Expression of Concern. See vol. 129, pg. 869, 2016) (Retracted article. See vol. 129, pg. 2685, 2016)
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DOI：
10.1242/jcs.073502
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发表时间：
2010-12-01
影响因子：
4
通讯作者：
Pastorino, John G.
中科院分区：
文献类型：
--
作者：
Shulga, Nataly;Pastorino, John G.
乙醇增加了线粒体诱导线粒体通透性转变（MPT）的脆弱性。亲环蛋白d活性增强了渗透性过渡孔（PTP）打开的可能性。在目前的研究中，我们证明了乙醇及其代谢使PTP对开放敏感，部分是通过增加乙酰化和亲环蛋白d的活性。乙醇的这种作用是通过抑制sirtuin-3的活性来介导的，sirtuin-3是一种依赖于线粒体基质的NAD（+）去乙酰化酶。乙醇增强的亲环蛋白d乙酰化也增加了亲环蛋白d与腺嘌呤核苷酸易位子-1 （ANT-1）的相互作用，并依赖于乙醇代谢。此外，AMPK（已知的sirtuin活性的正调节因子）的激活阻止了乙醇诱导的sirtuin-3活性的抑制以及随之而来的亲环蛋白d乙酰化、活性和与ANT-1的关联的增加。此外，AMPK对sirtuin-3的再激活阻止了暴露于乙醇的细胞对MPT的敏化和TNF对细胞杀伤的增强。
Ethanol increases the vulnerability of mitochondria to induction of the mitochondrial permeability transition (MPT). Cyclophilin-D activity enhances the potential for the permeability transition pore (PTP) to open. In the present study, we demonstrate that ethanol and its metabolism sensitize the PTP to opening, in part by increasing the acetylation and activity of cyclophilin-D. This effect of ethanol is mediated by inhibiting the activity of sirtuin-3, an NAD(+) dependent deacetylase that is localized to the mitochondrial matrix. The ethanol-enhanced acetylation of cyclophilin-D also increases the interaction of cyclophilin-D with the adenine nucleotide translocator-1 (ANT-1) and is dependent on ethanol metabolism. Moreover, activation of AMPK, a known positive modulator of sirtuin activity, prevented the ethanol-induced suppression of sirtuin-3 activity and the attendant increase of cyclophilin-D acetylation, activity and association with ANT-1. Additionally, AMPK reactivation of sirtuin-3 prevented the sensitization to the MPT and the enhancement of cell killing by TNF in cells exposed to ethanol.