Prohibitin levels regulate OMA1 activity and turnover in neurons
Prohibitin levels regulate OMA1 activity and turnover in neurons
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DOI：
10.1038/s41418-019-0469-4
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Iadecola, Costantino
中科院分区：
文献类型：
--
作者：
Anderson, Corey J.;Kahl, Anja;Iadecola, Costantino
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明确的作用。除了在线粒体膜融合、嵴结构和生物能功能中发挥作用外，OPA1 还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) 同工型的裂解会使线粒体融合失活并引发细胞凋亡。 OPA1 裂解受抑制素 (PHB) 复合物调节，PHB 复合物是一种由 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 对各种应激发挥保护作用，PHB 缺失会破坏 OPA1 的稳定性，从而导致神经退行性变。虽然 OMA1 的缺失可以防止 PHB2 KO 小鼠中 OPA1 不稳定并减轻神经变性，但 PHB 水平如何调节 OMA1 仍不清楚。在这里，我们研究调节神经元 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，有效减少 OMA1 池。此外，我们还发现 OMA1 与心磷脂 (CL) 结合，心磷脂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，我们发现 PHB 减少了 tBID 诱导的细胞色素 c 释放，并减弱了响应神经元缺氧应激的 caspase 9 激活。综上所述，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 释放来调节应激反应和细胞死亡。
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.