Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination.
Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination.
复制标题
DOI：
10.1038/s41598-020-74613-9
复制
发表时间：
2020-10-16
影响因子：
4.6
通讯作者：
Du H
中科院分区：
文献类型：
--
作者：
Chen H;Tian J;Guo L;Du H
树突棘损伤是许多神经系统疾病中突触失效的基础。越来越多的证据表明，介导脊柱修剪的局部非凋亡半胱天冬酶信号的线粒体途径。然而，目前尚不清楚这种caspase信号转导是否在严重线粒体功能缺陷时的脊柱丢失中起关键作用。这个问题的答案是至关重要的，特别是对于一些病理状态，其中线粒体缺陷是突出的，难以修复。F1 Fo ATP合成酶是一种重要的线粒体酶，其功能障碍与脊柱疾病有关。在这里，我们抑制F1 Fo ATP合酶功能在原代培养的海马神经元，通过使用非致死性寡霉素A治疗。寡霉素A诱导线粒体缺陷，包括线粒体膜电位崩溃，消耗ATP的生产，和活性氧（ROS）的生产增加。此外，树突状线粒体经历了增加的碎片化和减少的定位到树突棘沿着与增加的半胱天冬酶3裂解在树突状轴和棘响应寡霉素A。与这些树突状线粒体的变化，寡霉素A侮辱神经元显示脊柱损失和改变脊柱结构。这种寡霉素A介导的树突棘的变化基本上是通过使用泛半胱天冬酶抑制剂，喹啉基-缬氨酰-O-甲基缬氨酰-[-2，6-二氟苯氧基]-甲基酮（Q-VD-OPh）抑制半胱天冬酶活化来防止的。值得注意的是，施用Q-VD-OPh对寡霉素A诱导的线粒体功能障碍没有保护作用。我们的研究结果表明，在介导脊髓损伤和caspase 3激活的调制caspase 3信号转导的关键作用可能有利于神经元脊髓损失的疾病，至少在那些与F1 Fo ATP合酶缺陷。
Dendritic spine injury underlies synaptic failure in many neurological disorders. Mounting evidence suggests a mitochondrial pathway of local nonapoptotic caspase signaling in mediating spine pruning. However, it remains unclear whether this caspase signaling plays a key role in spine loss when severe mitochondrial functional defects are present. The answer to this question is critical especially for some pathological states, in which mitochondrial deficits are prominent and difficult to fix. F1Fo ATP synthase is a pivotal mitochondrial enzyme and the dysfunction of this enzyme involves in diseases with spinopathy. Here, we inhibited F1Fo ATP synthase function in primary cultured hippocampal neurons by using non-lethal oligomycin A treatment. Oligomycin A induced mitochondrial defects including collapsed mitochondrial membrane potential, dissipated ATP production, and elevated reactive oxygen species (ROS) production. In addition, dendritic mitochondria underwent increased fragmentation and reduced positioning to dendritic spines along with increased caspase 3 cleavage in dendritic shaft and spines in response to oligomycin A. Concurring with these dendritic mitochondrial changes, oligomycin A-insulted neurons displayed spine loss and altered spine architecture. Such oligomycin A-mediated changes in dendritic spines were substantially prevented by the inhibition of caspase activation by using a pan-caspase inhibitor, quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh). Of note, the administration of Q-VD-OPh showed no protective effect on oligomycin A-induced mitochondrial dysfunction. Our findings suggest a pivotal role of caspase 3 signaling in mediating spine injury and the modulation of caspase 3 activation may benefit neurons from spine loss in diseases, at least, in those with F1Fo ATP synthase defects.
登录
查看更多内容
影响因子：
16.2
作者：
Berry KP;Nedivi E
通讯作者：
Nedivi E
影响因子：
3.3
作者：
Dickstein, D. L.;Weaver, C. M.;Luebke, J. I.;Hof, P. R.
通讯作者：
Hof, P. R.
影响因子：
5.3
作者：
Ertuerk, Ali;Wang, Yuanyuan;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
7.7
作者：
Faits MC;Zhang C;Soto F;Kerschensteiner D
通讯作者：
Kerschensteiner D
影响因子：
64.5
作者：
Li, Z;Okamoto, K;Sheng, M
通讯作者：
Sheng, M