Mitochondrial fusion and Bid-mediated mitochondrial apoptosis are perturbed by alcohol with distinct dependence on its metabolism.
Mitochondrial fusion and Bid-mediated mitochondrial apoptosis are perturbed by alcohol with distinct dependence on its metabolism.
复制标题
DOI：
10.1038/s41419-018-1070-3
复制
发表时间：
2018-10-09
影响因子：
9
通讯作者：
Hajnóczky G
中科院分区：
文献类型：
--
作者：
Naghdi S;Slovinsky WS;Madesh M;Rubin E;Hajnóczky G
乙醇 (EtOH) 等环境压力通常会针对线粒体来影响细胞的命运。最近的文献支持，慢性乙醇暴露会抑制线粒体动力学（对于质量控制至关重要），并使线粒体通透性转换孔开放变得敏感，从而促进细胞死亡。乙醇引起的组织损伤主要归因于其有毒代谢产物，但酒精中毒也会损害乙醇代谢不良的组织。我们开始研究以确定 EtOH 及其代谢物在线粒体融合和 tBid 诱导的线粒体凋亡中各自的作用。我们使用不代谢乙醇的 HepG2 细胞及其表达乙醇代谢细胞色素 P450 E2 和乙醇脱氢酶的工程克隆（VL-17A 细胞）。我们发现，VL-17A 细胞中长期暴露于乙醇导致的融合损伤很明显，这可能是由于线粒体基质中活性氧的增加所致。融合蛋白丰度、线粒体膜电位或 Ca2+ 摄取没有变化。相比之下，由于 Bak 寡聚化增强，延长 EtOH 暴露仅在 HepG2 细胞中促进了 tBid 诱导的线粒体外膜透化和细胞死亡。因此，EtOH 对线粒体融合的抑制取决于其代谢物，而对 tBid 诱导的死亡的敏感性是由 EtOH 本身介导的。由于乙醇代谢的组织特异性差异，这种差异具有病理生理学相关性。
Environmental stressors like ethanol (EtOH) commonly target mitochondria to influence the cell’s fate. Recent literature supports that chronic EtOH exposure suppresses mitochondrial dynamics, central to quality control, and sensitizes mitochondrial permeability transition pore opening to promote cell death. EtOH-induced tissue injury is primarily attributed to its toxic metabolic products but alcoholism also impairs tissues that poorly metabolize EtOH. We embarked on studies to determine the respective roles of EtOH and its metabolites in mitochondrial fusion and tBid-induced mitochondrial apoptosis. We used HepG2 cells that do not metabolize EtOH and its engineered clone that expresses EtOH-metabolizing Cytochrome P450 E2 and alcohol dehydrogenase (VL-17A cells). We found that fusion impairment by prolonged EtOH exposure was prominent in VL-17A cells, probably owing to reactive oxygen species increase in the mitochondrial matrix. There was no change in fusion protein abundance, mitochondrial membrane potential or Ca2+ uptake. By contrast, prolonged EtOH exposure promoted tBid-induced outer mitochondrial membrane permeabilization and cell death only in HepG2 cells, owing to enhanced Bak oligomerization. Thus, mitochondrial fusion inhibition by EtOH is dependent on its metabolites, whereas sensitization to tBid-induced death is mediated by EtOH itself. This difference is of pathophysiological relevance because of the tissue-specific differences in EtOH metabolism.
登录
查看更多内容
DOI：
10.1111/acer.13473
发表时间：
2017-10
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Assiri MA;Roy SR;Harris PS;Ali H;Liang Y;Shearn CT;Orlicky DJ;Roede JR;Hirschey MD;Backos DS;Fritz KS
通讯作者：
Fritz KS
影响因子：
3.9
作者：
CLEMENS, DL;HALGARD, CM;TUMA, DJ
通讯作者：
TUMA, DJ
DOI：
10.1073/pnas.1118244109
发表时间：
2012-03-20
影响因子：
11.1
作者：
Garcia-Perez, Cecilia;Roy, Soumya Sinha;Hajnoczky, Gyoergy
通讯作者：
Hajnoczky, Gyoergy
影响因子：
48
作者：
Gutscher, Marcus;Pauleau, Anne-Laure;Dick, Tobias P.
通讯作者：
Dick, Tobias P.
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC