Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis

Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize...

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Autores principales:	Tom Kretzschmar, Mohamed M. Bekhite, Jasmine M. F. Wu, Daniela Haase, Martin Förster, Tina Müller, Sandor Nietzsche, Martin Westermann, Marcus Franz, Markus H. Gräler, P. Christian Schulze
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ceramides reactive oxygen species fibrosis mitochondrial function respiratory chain Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/6c46b5dcf5a94933a40b90adf86c3617
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spelling	oai:doaj.org-article:6c46b5dcf5a94933a40b90adf86c36172021-11-11T17:16:44ZLong-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis10.3390/ijms2221118521422-00671661-6596https://doaj.org/article/6c46b5dcf5a94933a40b90adf86c36172021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11852https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis.Tom KretzschmarMohamed M. BekhiteJasmine M. F. WuDaniela HaaseMartin FörsterTina MüllerSandor NietzscheMartin WestermannMarcus FranzMarkus H. GrälerP. Christian SchulzeMDPI AGarticleceramidesreactive oxygen speciesfibrosismitochondrial functionrespiratory chainBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11852, p 11852 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ceramides reactive oxygen species fibrosis mitochondrial function respiratory chain Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	ceramides reactive oxygen species fibrosis mitochondrial function respiratory chain Biology (General) QH301-705.5 Chemistry QD1-999 Tom Kretzschmar Mohamed M. Bekhite Jasmine M. F. Wu Daniela Haase Martin Förster Tina Müller Sandor Nietzsche Martin Westermann Marcus Franz Markus H. Gräler P. Christian Schulze Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis
description	Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis.
format	article
author	Tom Kretzschmar Mohamed M. Bekhite Jasmine M. F. Wu Daniela Haase Martin Förster Tina Müller Sandor Nietzsche Martin Westermann Marcus Franz Markus H. Gräler P. Christian Schulze
author_facet	Tom Kretzschmar Mohamed M. Bekhite Jasmine M. F. Wu Daniela Haase Martin Förster Tina Müller Sandor Nietzsche Martin Westermann Marcus Franz Markus H. Gräler P. Christian Schulze
author_sort	Tom Kretzschmar
title	Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis
title_short	Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis
title_full	Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis
title_fullStr	Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis
title_full_unstemmed	Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis
title_sort	long-chain and very long-chain ceramides mediate doxorubicin-induced toxicity and fibrosis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/6c46b5dcf5a94933a40b90adf86c3617
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Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis

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