From the Cell Death Regulation Group, IDIBELL (Bellvitge Biomedical Research Institute), L'Hospitalet de Llobregat, Barcelona, 08908 Spain.
the Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland, and.
J Biol Chem. 2013 Oct 18;288(42):30387-30398. doi: 10.1074/jbc.M113.490581. Epub 2013 Sep 6.
In response to nutrient shortage or organelle damage, cells undergo macroautophagy. Starvation of glucose, an essential nutrient, is thought to promote autophagy in mammalian cells. We thus aimed to determine the role of autophagy in cell death induced by glucose deprivation. Glucose withdrawal induces cell death that can occur by apoptosis (in Bax, Bak-deficient mouse embryonic fibroblasts or HeLa cells) or by necrosis (in Rh4 rhabdomyosarcoma cells). Inhibition of autophagy by chemical or genetic means by using 3-methyladenine, chloroquine, a dominant negative form of ATG4B or silencing Beclin-1, Atg7, or p62 indicated that macroautophagy does not protect cells undergoing necrosis or apoptosis upon glucose deprivation. Moreover, glucose deprivation did not induce autophagic flux in any of the four cell lines analyzed, even though mTOR was inhibited. Indeed, glucose deprivation inhibited basal autophagic flux. In contrast, the glycolytic inhibitor 2-deoxyglucose induced prosurvival autophagy. Further analyses indicated that in the absence of glucose, autophagic flux induced by other stimuli is inhibited. These data suggest that the role of autophagy in response to nutrient starvation should be reconsidered.
在应对营养物质短缺或细胞器损伤时，细胞会发生巨自噬。葡萄糖（一种必需营养物质）的饥饿被认为可促进哺乳动物细胞中的自噬。因此，我们旨在确定自噬在葡萄糖剥夺诱导的细胞死亡中的作用。葡萄糖剥夺会诱导细胞死亡，这种死亡可能通过细胞凋亡（在 Bax、Bak 缺陷型鼠胚胎成纤维细胞或 HeLa 细胞中）或坏死（在 Rh4 横纹肌肉瘤细胞中）发生。通过使用 3-甲基腺嘌呤、氯喹、ATG4B 的显性负形式或沉默 Beclin-1、Atg7 或 p62 等化学或遗传方法抑制自噬，表明巨自噬并不能保护在葡萄糖剥夺时发生坏死或凋亡的细胞。此外，即使抑制了 mTOR，在这四种分析的细胞系中，葡萄糖剥夺也没有诱导自噬通量。事实上，葡萄糖剥夺抑制了基础自噬通量。相比之下，糖酵解抑制剂 2-脱氧葡萄糖诱导了生存促进的自噬。进一步的分析表明，在没有葡萄糖的情况下，其他刺激诱导的自噬通量被抑制。这些数据表明，应重新考虑自噬在应对营养饥饿中的作用。
