Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
J Cell Sci. 2010 Dec 1;123(Pt 23):4117-27. doi: 10.1242/jcs.073502. Epub 2010 Nov 9.
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.
乙醇增加了线粒体对线粒体通透性转换（MPT）诱导的易感性。亲环素-D 活性增强了通透性转换孔（PTP）开放的潜力。在本研究中，我们证明乙醇及其代谢物通过增加亲环素-D 的乙酰化和活性，使 PTP 易于开放，部分原因是抑制了位于线粒体基质中的 NAD（+）依赖性去乙酰化酶 sirtuin-3 的活性。乙醇的这种作用是通过抑制 sirtuin-3 的活性介导的，sirtuin-3 是一种位于线粒体基质中的 NAD（+）依赖性去乙酰化酶。乙醇增强的亲环素-D 乙酰化作用也增加了亲环素-D 与腺嘌呤核苷酸转位酶-1（ANT-1）的相互作用，并且依赖于乙醇的代谢。此外，已知的 sirtuin 活性的正调节剂 AMPK 的激活，可防止乙醇诱导的 sirtuin-3 活性抑制以及随之而来的亲环素-D 乙酰化、活性和与 ANT-1 的关联增加。此外，AMPK 对 sirtuin-3 的再激活可防止在暴露于乙醇的细胞中对 MPT 的敏感性增加以及 TNF 增强的细胞杀伤。
