抑制素水平调节神经元中的 OMA1 活性和周转。,Cell Death and Differentiation

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抑制素水平调节神经元中的 OMA1 活性和周转。
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41418-019-0469-4
Corey J Anderson ₁ , Anja Kahl ₁ , Hannah Fruitman ₁ , Liping Qian ₁ , Ping Zhou ₁ , Giovanni Manfredi ₁ , Costantino Iadecola ₁

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GTPase OPA1 和 AAA 蛋白酶 OMA1 在线粒体应激反应和线粒体引发的细胞死亡中发挥着公认的作用。除了在线粒体膜融合、嵴结构和生物能功能中的作用外，OPA1 通过隔离线粒体嵴中的细胞色素 c (cyt c) 来控制细胞凋亡。OMA1 对功能性长 OPA1 (L-OPA1) 亚型的切割使线粒体融合失活并引发细胞凋亡。OPA1 切割受抑制素 (PHB) 复合物的调控，该复合物是由 PHB1 和 PHB2 组成的异聚环状线粒体内膜支架复合物。在神经元中，PHB 对各种压力起着保护作用，PHB 缺失会使 OPA1 不稳定，导致神经变性。虽然删除 OMA1 可防止 OPA1 不稳定并减轻 PHB2 KO 小鼠的神经变性，PHB 水平如何调节 OMA1 仍然未知。在这里，我们研究了调节神经元 PHB 水平对 OMA1 稳定性和 OPA1 裂解的影响。我们证明 PHB 促进 OMA1 周转，有效地减少了 OMA1 的池。此外，我们显示 OMA1 与心磷脂 (CL) 结合，这是一种主要的线粒体磷脂。CL 结合促进 OMA1 周转，因为我们表明删除 OMA1 的 CL 结合域会降低其周转率。由于已知 PHB 可以稳定 CL，因此这些数据表明 PHB 通过 CL 调节 OMA1。此外，我们表明 PHB 减少了 tBID 诱导的细胞色素 c 释放，并减弱了响应于神经元缺氧应激的 caspase 9 激活。总之，我们的结果表明，PHB 介导的 CL 稳定通过 OMA1 周转和细胞色素 c 释放调节应激反应和细胞死亡。

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Prohibitin levels regulate OMA1 activity and turnover in neurons.

The GTPase OPA1 and the AAA-protease OMA1 serve well-established roles in mitochondrial stress responses and mitochondria-initiated cell death. In addition to its role in mitochondrial membrane fusion, cristae structure, and bioenergetic function, OPA1 controls apoptosis by sequestering cytochrome c (cyt c) in mitochondrial cristae. Cleavage of functional long OPA1 (L-OPA1) isoforms by OMA1 inactivates mitochondrial fusion and primes apoptosis. OPA1 cleavage is regulated by the prohibitin (PHB) complex, a heteromeric, ring-shaped mitochondrial inner membrane scaffolding complex composed of PHB1 and PHB2. In neurons, PHB plays a protective role against various stresses, and PHB deletion destabilizes OPA1 causing neurodegeneration. While deletion of OMA1 prevents OPA1 destabilization and attenuates neurodegeneration in PHB2 KO mice, how PHB levels regulate OMA1 is still unknown. Here, we investigate the effects of modulating neuronal PHB levels on OMA1 stability and OPA1 cleavage. We demonstrate that PHB promotes OMA1 turnover, effectively decreasing the pool of OMA1. Further, we show that OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid. CL binding promotes OMA1 turnover, as we show that deleting the CL-binding domain of OMA1 decreases its turnover rate. Since PHB is known to stabilize CL, these data suggest that PHB modulates OMA1 through CL. Furthermore, we show that PHB decreases cyt c release induced by tBID and attenuates caspase 9 activation in response to hypoxic stress in neurons. Taken together, our results suggest that PHB-mediated CL stabilization regulates stress responses and cell death through OMA1 turnover and cyt c release.

更新日期：2019-12-09

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