The identity and regulation of the mitochondrial permeability transition pore - Where the known meets the unknown
The identity and regulation of the mitochondrial permeability transition pore - Where the known meets the unknown
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DOI：
10.1196/annals.1420.023
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发表时间：
2008-01-01
期刊：
影响因子：
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通讯作者：
Sollott, Steven J.
中科院分区：
文献类型：
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作者：
Juhaszova, Magdalena;Wang, Su;Sollott, Steven J.
线粒体渗透性转换（MPT）孔复合物是控制线粒体命运，从而控制细胞命运的机制的关键参与者。对孔隙特性的探索已经进行了几十年，但主要结构仍然未知。已建立的“教条”提出MPT孔的核心由电压依赖性阴离子通道（VDAC）和腺嘌呤核苷酸移位酶（ANT）的缔合组成。最近的基因敲除实验与这种普遍接受的解释相矛盾，并为MPT孔身份的实质性修订提供了基础。现在有足够的证据排除VDAC和ANT作为主要孔隙结构组分。关于MPT孔调节，亲环素D的作用得到证实，ANT可能仍然具有一定的调节功能，尽管己糖激酶II和肌酸激酶的参与仍未得到解决。当细胞保护信号通路被激活时，我们发现Bcl-2家族成员将来自糖原合成酶激酶-3 β的信号传递到孔处或孔附近的靶标上。我们在完整的心肌细胞和神经元的实验结果表明，目前的“教条”有关的作用，Ca 2+在MPT诱导需要重新评估。新出现的证据表明，损伤后产生的应力，活性氧（但不是Ca 2+）在很大程度上负责孔诱导。在这篇文章中，我们讨论了目前的知识状况，并提供了新的数据有关的NIPT孔结构和调节。
The mitochondrial permeability transition (MPT) pore complex is a key participant in the machinery that controls mitochondrial fate and, consequently, cell fate. The quest for the pore identity has been ongoing for several decades and yet the main structure remains unknown. Established "dogma" proposes that the core of the MPT pore is composed of an association of voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT). Recent genetic knockout experiments contradict this commonly accepted interpretation and provide a basis for substantial revision of the MPT pore identity. There is now sufficient evidence to exclude VDAC and ANT as the main pore structural components. Regarding MPT pore regulation, the role of cyclophilin D is confirmed and ANT may still serve some regulatory function, although the involvement of hexokinase II and creatine kinase remains unresolved. When cell protection signaling pathways are activated, we have found that the Bcl-2 family members relay the signal from glycogen synthase kinase-3 beta onto a target at or in close proximity to the pore. Our experimental findings in intact cardiac myocytes and neurons indicate that the current "dogma" related to the role of Ca2+ in MPT induction requires reevaluation. Emerging evidence suggests that after injury-producing stresses, reactive oxygen species (but not Ca2+) are largely responsible for the pore induction. In this article we discuss the current state of knowledge and provide new data related to the NIPT pore structure and regulation.