Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization.
Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization.
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DOI：
10.1038/srep35907
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发表时间：
2016-10-27
影响因子：
4.6
通讯作者：
Burke PJ
中科院分区：
文献类型：
--
作者：
Pham TD;Pham PQ;Li J;Letai AG;Wallace DC;Burke PJ
内源性凋亡途径和由此产生的线粒体外膜透化（MOMP）通过巴克和BAX寡聚化，细胞色素c（cytc）的释放，和半胱天冬酶激活的研究很好，但其对细胞溶质pH值的影响知之甚少。使用分离的线粒体，我们表明，MOMP导致周围介质的酸化。与MOMP相关的巴克构象变化激活OMA1蛋白酶以切割OPA1，导致嵴的重塑和嵴内陷内高度浓缩的质子的释放。这是通过利用纳米材料石墨烯作为光学透明和超灵敏的pH传感器来揭示的，该传感器可以测量由拴系的线粒体引起的离子变化。通过这个平台，我们发现线粒体凋亡的激活伴随着线粒体外pH的逐渐下降和膜电位的下降，这两者都可以通过添加外源性cytc来挽救。这些发现对于肿瘤治疗中细胞凋亡的潜在药理学操作具有重要意义。
The intrinsic apoptotic pathway and the resultant mitochondrial outer membrane permeabilization (MOMP) via BAK and BAX oligomerization, cytochrome c (cytc) release, and caspase activation are well studied, but their effect on cytosolic pH is poorly understood. Using isolated mitochondria, we show that MOMP results in acidification of the surrounding medium. BAK conformational changes associated with MOMP activate the OMA1 protease to cleave OPA1 resulting in remodeling of the cristae and release of the highly concentrated protons within the cristae invaginations. This was revealed by utilizing a nanomaterial graphene as an optically clear and ultrasensitive pH sensor that can measure ionic changes induced by tethered mitochondria. With this platform, we have found that activation of mitochondrial apoptosis is accompanied by a gradual drop in extra-mitochondrial pH and a decline in membrane potential, both of which can be rescued by adding exogenous cytc. These findings have importance for potential pharmacological manipulation of apoptosis, in the treatment of cancer.
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影响因子：
3.7
作者：
Frank DO;Dengjel J;Wilfling F;Kozjak-Pavlovic V;Häcker G;Weber A
通讯作者：
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通讯作者：
Bootman, MD
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作者：
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Peluso, G