1-Deoxydihydroceramide causes anoxic death by impairing chaperonin-mediated protein folding.

Nature Metabolism
J Thomas HannichHoward Riezman

Abstract

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.

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Citations

Apr 16, 2020·Angewandte Chemie·Carla KirschbaumKevin Pagel
Dec 22, 2019·The Journal of Biological Chemistry·Gergely KarsaiThorsten Hornemann
Nov 13, 2020·Science Advances·Rupali PrasadYves Barral
Aug 8, 2021·International Journal of Molecular Sciences·Essa M Saied, Christoph Arenz
Aug 14, 2021·Nature Communications·Carla E Cadena Del CastilloAnne Spang

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