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Open AccessArticle

Doxorubicin Inhibits Phosphatidylserine Decarboxylase and Modifies Mitochondrial Membrane Composition in HeLa Cells

1
INSERM U1211, Rare Diseases: Genetic and Metabolism, F-33076 Bordeaux, France
2
University of Bordeaux, F-33076 Bordeaux, France
3
UMR 5200 CNRS, Membrane Biogenesis Laboratory, F-33140 Villenave d’Ornon, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1317; https://doi.org/10.3390/ijms21041317
Received: 6 January 2020 / Revised: 11 February 2020 / Accepted: 13 February 2020 / Published: 15 February 2020
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II. However, few studies have reported the mitochondrial effects of DXR while investigating cardiac toxicity induced by the treatment, mostly in pediatric cases. Here, we demonstrate that DXR alters the mitochondrial membrane composition associated with bioenergetic impairment and cell death in human cancer cells. The remodeling of the mitochondrial membrane was explained by phosphatidylserine decarboxylase (PSD) inhibition by DXR. PSD catalyzes phosphatidylethanolamine (PE) synthesis from phosphatidylserine (PS), and DXR altered the PS/PE ratio in the mitochondrial membrane. Moreover, we observed that DXR localized to the mitochondrial compartment and drug uptake was rapid. Evaluation of other topoisomerase II inhibitors did not show any impact on the mitochondrial membrane composition, indicating that the DXR effect was specific. Therefore, our findings revealed a side molecular target for DXR and PSD, potentially involved in DXR anti-cancer properties and the associated toxicity. View Full-Text
Keywords: phosphatidylserine decarboxylase; doxorubicin; bioenergetics; phosphatidylethanolamine phosphatidylserine decarboxylase; doxorubicin; bioenergetics; phosphatidylethanolamine
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Bellance, N.; Furt, F.; Melser, S.; Lalou, C.; Thoraval, D.; Maneta-Peyret, L.; Lacombe, D.; Moreau, P.; Rossignol, R. Doxorubicin Inhibits Phosphatidylserine Decarboxylase and Modifies Mitochondrial Membrane Composition in HeLa Cells. Int. J. Mol. Sci. 2020, 21, 1317.

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