Cytotoxicity of 1-deoxysphingolipid Unraveled by Genome-wide Genetic Screens and Lipidomics in

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2019 Sep 12

PMID 31509475

Citations 10

Authors

A Galih Haribowo

J Thomas Hannich

Agnes H Michel

Marton Megyeri

Maya Schuldiner

Benoit Kornmann

Howard Riezman

Affiliations

Soon will be listed here.

Abstract

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 C-1-deoxydihydroceramide (C-DoxDHCer) is highly toxic to the cell, while C- and C-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.

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