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1-Deoxydihydroceramide causes anoxic death by impairing chaperonin-mediated protein folding.
Nature Metabolism ( IF 20.8 ) Pub Date : 2019-10-14 , DOI: 10.1038/s42255-019-0123-y
J Thomas Hannich 1, 2 , A Galih Haribowo 1, 2 , Sébastien Gentina 3 , Melanie Paillard 4 , Ludovic Gomez 4 , Bruno Pillot 4 , Hélène Thibault 4 , Daniel Abegg 5 , Nicolas Guex 6, 7 , Andreas Zumbuehl 2, 8 , Alexander Adibekian 5 , Michel Ovize 4 , Jean-Claude Martinou 3 , Howard Riezman 1, 2
Affiliation  

Ischaemic heart disease and stroke are the most common causes of death worldwide. Anoxia, defined as the lack of oxygen, is commonly seen in both these pathologies and triggers profound metabolic and cellular changes. Sphingolipids have been implicated in anoxia injury, but the pathomechanism is unknown. Here we show that anoxia-associated injury causes accumulation of the non-canonical sphingolipid 1-deoxydihydroceramide (DoxDHCer). Anoxia causes an imbalance between serine and alanine resulting in a switch from normal serine-derived sphinganine biosynthesis to non-canonical alanine-derived 1-deoxysphinganine. 1-Deoxysphinganine is incorporated into DoxDHCer, which impairs actin folding via the cytosolic chaperonin TRiC, leading to growth arrest in yeast, increased cell death upon anoxia–reoxygenation in worms and ischaemia–reperfusion injury in mouse hearts. Prevention of DoxDHCer accumulation in worms and in mouse hearts resulted in decreased anoxia-induced injury. These findings unravel key metabolic changes during oxygen deprivation and point to novel strategies to avoid tissue damage and death.



中文翻译:

1-脱氧二氢神经酰胺通过破坏伴侣蛋白介导的蛋白质折叠而导致缺氧性死亡。

缺血性心脏病和中风是全世界最常见的死亡原因。厌氧症定义为缺氧,在这两种病理中都很常见,并引发深刻的代谢和细胞变化。鞘脂与缺氧性损伤有关,但其致病机理尚不清楚。在这里,我们显示与缺氧相关的损伤会引起非规范性鞘脂1-脱氧二氢神经酰胺(DoxDHCer)的积累。缺氧会导致丝氨酸和丙氨酸之间的不平衡,从而导致从正常的丝氨酸衍生的鞘氨醇生物合成转变为非规范的丙氨酸衍生的1-脱氧鞘氨醇。将1-Deoxysphinganine掺入DoxDHCer中,从而通过胞质伴侣蛋白TRiC破坏肌动蛋白折叠,从而导致酵母中的生长停滞,蠕虫中的缺氧-复氧和小鼠心脏的局部缺血-再灌注损伤会增加细胞死亡。预防DoxDHCer在蠕虫和小鼠心脏中的蓄积可减少缺氧引起的损伤。这些发现揭示了缺氧期间关键的代谢变化,并指出了避免组织损伤和死亡的新策略。

更新日期:2019-10-14
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