Journal
BIOSCIENCE REPORTS
Volume 42, Issue 2, Pages -Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BSR20212433
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Funding
- Japan Society for the Promotion of Science [19H03375, 25116720]
- Private University High Technology Research Center Project from the Ministry of Education, Culture, Sports, Science, Culture and Technology of Japan
- Grants-in-Aid for Scientific Research [19H03375] Funding Source: KAKEN
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In this study, ACSL4 knockdown was found to decrease the levels of PUFA-derived acyl-CoA, particularly leading to a decrease in DHA-containing phospholipids. This inhibition further suppressed cell death induced by ferroptosis.
Acyl-CoA synthetase long-chain family member 4 (ACSL4) activates polyunsaturated fatty acids (PUFAs) to produce PUFA-derived acyl-CoAs, which are utilised for the synthesis of various biological components, including phospholipids (PLs). Although the roles of ACSL4 in non-apoptotic programmed cell death ferroptosis are well-characterised, its role in the other types of cell death is not fully understood. In the present study, we investigated the effects of ACSL4 knockdown on the levels of acyl-CoA, PL, and ferroptosis in the human spectrometry (LC-MS/MS) analyses revealed that the knockdown of ACSL4 markedly reduced the levels of PUFA-derived acyl-CoA, but not those of other acyl-CoAs. In contrast with acyl-CoA levels, the docosahexaenoic acid (DHA)-containing PL levels were preferentially decreased in the ACSL4-knockdown cells compared with the control cells. Cell death induced by the ferroptosis inducers RSL3 and FIN56 was significantly suppressed by treatment with ferrostatin-1 or ACSL4 knockdown, and, unexpectedly, upon treating with a necroptosis inhibitor. In contrast, ACSL4 knockdown failed to suppress the other oxidative stress-induced cell deaths initiated by cadmium chloride and sodium arsenite. In conclusion, ACSL4 is involved in the biosynthesis of DHA-containing PLs in HK-2 cells and is specifically involved in the cell death induced by ferroptosis inducers.
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