Dual dynamics of mitochondrial permeability transition pore opening
Dual dynamics of mitochondrial permeability transition pore opening
复制标题
DOI：
10.1038/s41598-020-60177-1
复制
发表时间：
2020-03-03
影响因子：
4.6
通讯作者：
Dupont, Genevieve
中科院分区：
文献类型：
--
作者：
Wacquier, Benjamin;Combettes, Laurent;Dupont, Genevieve
线粒体在生物能量学和细胞内钙处理中起着重要作用。线粒体通透性转换孔(MPTP)是位于线粒体内膜上的一种非特异性通道。长时间的毛孔开口允许离子和大分子快速通过，这可能导致细胞死亡。MPTP还表现出瞬间的低电导开放，有助于钙离子的动态平衡。尽管已经确定了许多毛孔的调节器，但它们中没有一个是唯一地管理两种运行模式之间的通道，因此这可能依赖于一个仍未确定的相互作用网络。通过建立线粒体电压和钙离子控制下MPTP开放的核心计算模型，我们发现了导致双稳的正反馈回路的存在。两个稳定稳态的特征与两个开态的特征相对应。当插入线粒体处理钙离子的完整模型时，我们对孔洞的描述重现了线粒体悬浮液中的观察结果。此外，该模型预测了在线粒体外介质中添加和移除游离钙时，在两种模式之间切换时会出现滞后。随机模拟随后证实，毛孔可以经历与在完整细胞中观察到的类似的瞬时开口。
Mitochondria play an essential role in bioenergetics and cellular Ca2+ handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca2+ homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca2+, we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca2+ handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca2+ in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.