MEC17-induced alpha-tubulin acetylation restores mitochondrial transport function and alleviates axonal injury after intracerebral hemorrhage in mice
MEC17-induced alpha-tubulin acetylation restores mitochondrial transport function and alleviates axonal injury after intracerebral hemorrhage in mice
复制标题
MEC17诱导的α微管蛋白乙酰化可恢复小鼠脑出血后线粒体转运功能并减轻轴突损伤
DOI：
10.1111/jnc.15493
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发表时间：
2022
影响因子：
4.7
通讯作者：
Feng Hua
中科院分区：
文献类型：
--
作者：
Yang Yang;Chen Xuezhu;Feng Zhizhong;Cai Xianfeng;Zhu Xiaoming;Cao Ming;Yang Likun;Chen Yujie;Wang Yuhai;Feng Hua
长轴突突起损伤是脑出血（ICH）早期的主要病理特征。据报道，它会导致脑出血后持续的功能障碍。然而，驱动轴突变性的分子机制仍不清楚。将自体血液注入纹状体以模拟脑出血的病理学。 ICH 后 24 小时，在纹状体血肿周围发现明显肿胀的轴突，并具有特征性的回缩球。电子显微镜检查显示回缩球中的微管高度紊乱，线粒体肿胀。 MEC17是一种特异性的α微管蛋白乙酰转移酶，MEC17−/−小鼠中乙酰化α微管蛋白的消融会加重轴突损伤、轴突运输线粒体功能障碍和运动功能障碍。相比之下，图巴他汀 A (TubA) 治疗可促进微管乙酰化，显着减轻轴突损伤，并保护 ICH 后皮质脊髓束的完整性和精细运动功能。此外，结果表明，41% 的线粒体优先与原代神经元中可识别的轴突和树突中的乙酰化 α-微管蛋白结合。这损害了 MEC17−/− 小鼠原代神经元中线粒体的轴突运输。鉴于线粒体通透性转换孔（mPTP）的开放会诱导线粒体功能障碍并损害 ATP 供应，从而促进轴突损伤，我们使用 TubA 增强乙酰化 α-微管蛋白的可用性，并使用环孢素 A 抑制 mPTP 开放。结果表明，这种联合治疗可协同保护皮质脊髓束的完整性并促进精细 电机控制恢复。这些发现揭示了 ICH 后驱动轴突变性的关键细胞内机制，并强调需要针对多种因素和各自的调节机制作为预防 ICH 后轴突变性和运动功能障碍的有效方法。
Injury to long axonal projections is a central pathological feature at the early phase of intracerebral hemorrhage (ICH). It has been reported to contribute to persistent functional disability following ICH. However, the molecular mechanisms that drive axonal degeneration remain unclear. Autologous blood was injected into the striatum to mimic the pathology of ICH. Observed significant swollen axons with characteristic retraction bulbs were found around the striatal hematoma at 24 h after ICH. Electronic microscopic examination revealed highly disorganized microtubule and swollen mitochondria in the retraction bulbs. MEC17 is a specific α‐tubulin acetyltransferase, ablation of acetylated α‐tubulin inMEC17−/−mice aggravated axonal injury, axonal transport mitochondria dysfunction, and motor dysfunction. In contrast, treatment with tubastatin A (TubA), which promotes microtubule acetylation, significantly alleviated axonal injury and protected the integrity of the corticospinal tract and fine motor function after ICH. Moreover, results showed that 41% mitochondria were preferentially bundled to the acetylated α‐tubulin in identifiable axons and dendrites in primary neurons. This impaired axonal transport of mitochondria in primary neurons ofMEC17−/−mice. Given that opening of mitochondrial permeability transition pore (mPTP) induces mitochondrial dysfunction and impairs ATP supply thereby promoting axonal injury, we enhanced the availability of acetylated α‐tubulin using TubA and inhibited mPTP opening with cyclosporin A. The results indicated that this combined treatment synergistically protected corticospinal tract integrity and promoted fine motor control recovery. These findings reveal key intracellular mechanisms that drive axonal degeneration after ICH and highlight the need to target multiple factors and respective regulatory mechanisms as an effective approach to prevent axonal degeneration and motor dysfunction after ICH.