Activation of autophagy via Ca2+-dependent AMPK/mTOR pathway in rat notochordal cells is a cellular adaptation under hyperosmotic stress
Activation of autophagy via Ca2+-dependent AMPK/mTOR pathway in rat notochordal cells is a cellular adaptation under hyperosmotic stress
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大鼠脊索细胞中 Ca2 依赖的 AMPK/mTOR 通路激活自噬是高渗应激下的细胞适应
DOI：
10.1080/15384101.2015.1004946
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发表时间：
2015-03-15
期刊：
影响因子：
4.3
通讯作者：
Li, Xi-Lei
中科院分区：
文献类型：
--
作者：
Jiang, Li-Bo;Cao, Lu;Li, Xi-Lei
髓核（NP）细胞在椎间盘中经历高渗应力;然而，这些细胞如何在不利的微环境中存活仍不清楚。自噬通过降解细胞质蛋白和细胞器来维持细胞在不同胁迫下的稳态。在这里，我们探讨了自噬是否是高渗应激下大鼠脊索细胞的细胞适应。高渗应激以剂量和时间依赖性方式激活自噬。SQSTM 1/P62表达随自噬水平的增加而降低。高渗应激可刺激细胞内钙库和细胞外钙的瞬时内流。在高渗条件下，AMPK被激活，p70 S6 K被抑制。而胞间Ca ~（2+）螯合抑制了LC_3-Ⅱ的升高，部分逆转了p70 S_6 K的降低。高渗胁迫降低细胞活力，促进细胞凋亡。抑制自噬导致SQSTM 1/P62的积累，降低细胞活力，并在这种条件下加速脊索细胞的凋亡。这些证据表明，自噬诱导通过Ca 2+依赖的AMPK/mTOR途径可能发生作为一种适应机制，脊索细胞在高渗胁迫下。因此，激活自噬可能是提高椎间盘脊索细胞活力的一种有前途的方法。
Nucleus pulposus (NP) cells experience hyperosmotic stress in spinal discs; however, how these cells can survive in the hostile microenvironment remains unclear. Autophagy has been suggested to maintain cellular homeostasis under different stresses by degrading the cytoplasmic proteins and organelles. Here, we explored whether autophagy is a cellular adaptation in rat notochordal cells under hyperosmotic stress. Hyperosmotic stress was found to activate autophagy in a dose- and time-dependent manner. SQSTM1/P62 expression was decreased as the autophagy level increased. Transient Ca2+ influx from intracellular stores and extracellular space was stimulated by hyperosmotic stress. Activation of AMPK and inhibition of p70S6K were observed under hyperosmotic conditions. However, intercellular Ca2+ chelation inhibited the increase of LC3-II and partly reversed the decrease of p70S6K. Hyperosmotic stress decreased cell viability and promoted apoptosis. Inhibition of autophagy led to SQSTM1/P62 accumulation, reduced cell viability, and accelerated apoptosis in notochordal cells under this condition. These evidences suggest that autophagy induction via the Ca2+-dependent AMPK/mTOR pathway might occur as an adaptation mechanism for notochordal cells under hyperosmotic stress. Thus, activating autophagy might be a promising approach to improve viability of notochordal cells in intervertebral discs.