The lipid flippase ATP10B enables cellular lipid uptake under stress conditions

Rosanne Wouters; Igor Beletchi; Chris Van den Haute; Veerle Baekelandt; Shaun Martin; Jan Eggermont; Peter Vangheluwe

doi:10.1016/j.bbamcr.2023.119652

The lipid flippase ATP10B enables cellular lipid uptake under stress conditions

Biochim Biophys Acta Mol Cell Res. 2024 Feb;1871(2):119652. doi: 10.1016/j.bbamcr.2023.119652. Epub 2023 Dec 11.

Authors

Rosanne Wouters¹, Igor Beletchi², Chris Van den Haute³, Veerle Baekelandt⁴, Shaun Martin², Jan Eggermont², Peter Vangheluwe⁵

Affiliations

¹ Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
² Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium.
³ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Leuven Viral Vector Core, KU Leuven, B-3000 Leuven, Belgium; Research Group for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B-3000 Leuven, Belgium.
⁴ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Research Group for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B-3000 Leuven, Belgium.
⁵ Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA. Electronic address: peter.vangheluwe@kuleuven.be.

PMID: 38086447
DOI: 10.1016/j.bbamcr.2023.119652

Abstract

Pathogenic ATP10B variants have been described in patients with Parkinson's disease and dementia with Lewy body disease, and we previously established ATP10B as a late endo-/lysosomal lipid flippase transporting both phosphatidylcholine (PC) and glucosylceramide (GluCer) from the lysosomal exoplasmic to cytoplasmic membrane leaflet. Since several other lipid flippases regulate cellular lipid uptake, we here examined whether also ATP10B impacts cellular lipid uptake. Transient co-expression of ATP10B with its obligatory subunit CDC50A stimulated the uptake of fluorescently (NBD-) labeled PC in HeLa cells. This uptake is dependent on the transport function of ATP10B, is impaired by disease-associated variants and appears specific for NBD-PC. Uptake of non-ATP10B substrates, such as NBD-sphingomyelin or NBD-phosphatidylethanolamine is not increased. Remarkably, in stable cell lines co-expressing ATP10B/CDC50A we only observed increased NBD-PC uptake following treatment with rotenone, a mitochondrial complex I inhibitor that induces transport-dependent ATP10B phenotypes. Conversely, Im95m and WM-115 cells with endogenous ATP10B expression, present a decreased NBD-PC uptake following ATP10B knockdown, an effect that is exacerbated under rotenone stress. Our data show that the endo-/lysosomal lipid flippase ATP10B contributes to cellular PC uptake under specific cell stress conditions.

Keywords: Endo-/lysosomes; Glucosylceramide; Lipid transport; Parkinson's disease; Phosphatidylcholine.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Biological Transport
Cell Membrane / metabolism
HeLa Cells
Humans
Rotenone* / pharmacology

Substances

Rotenone