Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening.
Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening.
复制标题
DOI：
10.1074/jbc.m109.025353
复制
发表时间：
2009-07-31
期刊：
影响因子：
--
通讯作者：
Gerasimenko OV
中科院分区：
文献类型：
--
作者：
Baumgartner HK;Gerasimenko JV;Thorne C;Ferdek P;Pozzan T;Tepikin AV;Petersen OH;Sutton R;Watson AJ;Gerasimenko OV
我们已经详细研究了细胞器内Ca 2+含量在氧化剂甲萘醌诱导细胞凋亡过程中的作用，同时改变和监测内质网（ER），线粒体和酸性细胞器的Ca 2+负荷。甲萘醌引起活性氧的产生，诱导氧化应激，随后引起细胞凋亡。在胰腺腺泡和胰腺肿瘤AR 42 J细胞中，甲萘醌被发现诱导重复的胞质Ca 2+反应，因为Ca 2+从ER和酸性储存中释放。Ca 2+对甲萘醌的反应伴随着线粒体中Ca 2+的升高、线粒体去极化和线粒体通透性转换孔（mPTP）的开放。排空ER和酸性Ca 2+储存并不一定能阻止甲萘醌诱导的细胞凋亡。高线粒体Ca 2+在甲萘醌应用的时间是决定细胞命运的主要因素。然而，如果用10 μm RU 360阻止线粒体加载Ca 2+，则无论其他Ca 2+储存的含量如何，caspase-9都不会激活。这些结果证实了线粒体内钙与pericam的比率测量。我们得出结论，线粒体中Ca 2+升高是决定细胞是否发生氧化应激诱导凋亡的关键因素。
We have investigated in detail the role of intra-organelle Ca2+ content during induction of apoptosis by the oxidant menadione while changing and monitoring the Ca2+ load of endoplasmic reticulum (ER), mitochondria, and acidic organelles. Menadione causes production of reactive oxygen species, induction of oxidative stress, and subsequently apoptosis. In both pancreatic acinar and pancreatic tumor AR42J cells, menadione was found to induce repetitive cytosolic Ca2+ responses because of the release of Ca2+ from both ER and acidic stores. Ca2+ responses to menadione were accompanied by elevation of Ca2+ in mitochondria, mitochondrial depolarization, and mitochondrial permeability transition pore (mPTP) opening. Emptying of both the ER and acidic Ca2+ stores did not necessarily prevent menadione-induced apoptosis. High mitochondrial Ca2+ at the time of menadione application was the major factor determining cell fate. However, if mitochondria were prevented from loading with Ca2+ with 10 μm RU360, then caspase-9 activation did not occur irrespective of the content of other Ca2+ stores. These results were confirmed by ratiometric measurements of intramitochondrial Ca2+ with pericam. We conclude that elevated Ca2+ in mitochondria is the crucial factor in determining whether cells undergo oxidative stress-induced apoptosis.