Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae
Hereditary sensory and autonomic neuropathy (HSAN) types IA and IC (IA/C) are caused by elevated levels of an atypical class of lipid named 1-deoxysphingolipid (DoxSL). How elevated levels of DoxSL perturb the physiology of the cell and how the perturbations lead to HSAN IA/C are largely unknown. In...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Cell Biology
2019
|
| _version_ | 1797063652040245248 |
|---|---|
| author | Haribowo, AG Hannich, JT Michel, AH Megyeri, M Schuldiner, M Kornmann, B Riezman, H |
| author_facet | Haribowo, AG Hannich, JT Michel, AH Megyeri, M Schuldiner, M Kornmann, B Riezman, H |
| author_sort | Haribowo, AG |
| collection | OXFORD |
| description | Hereditary sensory and autonomic neuropathy (HSAN) types IA and IC (IA/C) are caused by elevated levels of an atypical class of lipid named 1-deoxysphingolipid (DoxSL). How elevated levels of DoxSL perturb the physiology of the cell and how the perturbations lead to HSAN IA/C are largely unknown. In this study, we show that C26-1-deoxydihydroceramide (C26-DoxDHCer) is highly toxic to the cell, while C16- and C18-DoxDHCer are less toxic. Genome-wide genetic screens and lipidomics revealed the dynamics of DoxSL accumulation and DoxSL species responsible for the toxicity over the course of DoxSL accumulation. Moreover, we show that disruption of F-actin organization, alteration of mitochondrial shape, and accumulation of hydrophobic bodies by DoxSL are not sufficient to cause complete cellular failure. We found that cell death coincides with collapsed ER membrane, although we cannot rule out other possible causes of cell death. Thus, we have unraveled key principles of DoxSL cytotoxicity that may help to explain the clinical features of HSAN IA/C. |
| first_indexed | 2024-03-06T21:02:59Z |
| format | Journal article |
| id | oxford-uuid:3b7d102b-9fa8-47dc-ae42-b893b3470be9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:02:59Z |
| publishDate | 2019 |
| publisher | American Society for Cell Biology |
| record_format | dspace |
| spelling | oxford-uuid:3b7d102b-9fa8-47dc-ae42-b893b3470be92022-03-26T14:07:57ZCytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiaeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3b7d102b-9fa8-47dc-ae42-b893b3470be9EnglishSymplectic ElementsAmerican Society for Cell Biology2019Haribowo, AGHannich, JTMichel, AHMegyeri, MSchuldiner, MKornmann, BRiezman, HHereditary sensory and autonomic neuropathy (HSAN) types IA and IC (IA/C) are caused by elevated levels of an atypical class of lipid named 1-deoxysphingolipid (DoxSL). How elevated levels of DoxSL perturb the physiology of the cell and how the perturbations lead to HSAN IA/C are largely unknown. In this study, we show that C26-1-deoxydihydroceramide (C26-DoxDHCer) is highly toxic to the cell, while C16- and C18-DoxDHCer are less toxic. Genome-wide genetic screens and lipidomics revealed the dynamics of DoxSL accumulation and DoxSL species responsible for the toxicity over the course of DoxSL accumulation. Moreover, we show that disruption of F-actin organization, alteration of mitochondrial shape, and accumulation of hydrophobic bodies by DoxSL are not sufficient to cause complete cellular failure. We found that cell death coincides with collapsed ER membrane, although we cannot rule out other possible causes of cell death. Thus, we have unraveled key principles of DoxSL cytotoxicity that may help to explain the clinical features of HSAN IA/C. |
| spellingShingle | Haribowo, AG Hannich, JT Michel, AH Megyeri, M Schuldiner, M Kornmann, B Riezman, H Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae |
| title | Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae |
| title_full | Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae |
| title_fullStr | Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae |
| title_full_unstemmed | Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae |
| title_short | Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae |
| title_sort | cytotoxicity of 1 deoxysphingolipid unraveled by genome wide genetic screens and lipidomics in saccharomyces cerevisiae |
| work_keys_str_mv | AT haribowoag cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae AT hannichjt cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae AT michelah cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae AT megyerim cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae AT schuldinerm cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae AT kornmannb cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae AT riezmanh cytotoxicityof1deoxysphingolipidunraveledbygenomewidegeneticscreensandlipidomicsinsaccharomycescerevisiae |