MCL-1Matrix maintains neuronal survival by enhancing mitochondrial integrity and bioenergetic capacity under stress conditions
MCL-1Matrix maintains neuronal survival by enhancing mitochondrial integrity and bioenergetic capacity under stress conditions
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MCL-1Matrix在应激条件下通过增强线粒体完整性和生物能量能力维持神经元存活
DOI：
10.1038/s41419-020-2498-9
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发表时间：
2020-05-05
影响因子：
9
通讯作者：
Slack, Ruth S.
中科院分区：
文献类型：
--
作者：
Anilkumar, Ujval;Khacho, Mireille;Slack, Ruth S.
线粒体通过有效的能量代谢在神经元存活中起着至关重要的作用。在病理条件下，线粒体应激导致神经元死亡，其由抗凋亡BCL-2蛋白家族调节。MCL-1是一种抗凋亡BCL-2蛋白，定位于线粒体的外膜（OM）或内膜（Matrix）中，它们分别在抑制凋亡和促进生物能量学方面具有不同的作用。虽然Mcl 1的抗凋亡作用得到了很好的表征，但对MCL-1（Matrix）的保护功能仍然知之甚少。在这里，我们表明MCL-1（OM）和MCL-1（基质）通过不同的机制防止神经元死亡。我们报告说，MCL-1（矩阵）的功能，以保持线粒体的能量转导，并提高呼吸链的能力，通过调节线粒体耗氧量响应线粒体应激。我们发现，MCL-1（基质）保护神经元从压力，通过增强呼吸功能，并通过抑制线粒体通透性转换孔开放。总之，我们的研究结果提供了新的见解MCL-1（基质）如何在涉及线粒体功能丧失的应激条件下赋予神经保护作用。
Mitochondria play a crucial role in neuronal survival through efficient energy metabolism. In pathological conditions, mitochondrial stress leads to neuronal death, which is regulated by the anti-apoptotic BCL-2 family of proteins. MCL-1 is an anti-apoptotic BCL-2 protein localized to mitochondria either in the outer membrane (OM) or inner membrane (Matrix), which have distinct roles in inhibiting apoptosis and promoting bioenergetics, respectively. While the anti-apoptotic role for Mcl1 is well characterized, the protective function of MCL-1 (Matrix) remains poorly understood. Here, we show MCL-1(OM) and MCL-1(Matrix) prevent neuronal death through distinct mechanisms. We report that MCL-1(Matrix) functions to preserve mitochondrial energy transduction and improves respiratory chain capacity by modulating mitochondrial oxygen consumption in response to mitochondrial stress. We show that MCL-1(Matrix) protects neurons from stress by enhancing respiratory function, and by inhibiting mitochondrial permeability transition pore opening. Taken together, our results provide novel insight into how MCL-1(Matrix) may confer neuroprotection under stress conditions involving loss of mitochondrial function.