Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis

Aiden Haghikia; Simon Faissner; Derek Pappas; Bartosz Pula; Denis A. Akkad; Larissa Arning; Sabrina Ruhrmann; Alexander Duscha; Ralf Gold; Sergio E. Baranzini; Sunny Malhotra; Xavier Montalban; Manuel Comabella; Andrew Chan

doi:10.1177/1352458514561909

Interferon-beta affects mitochondrial activity in CD4⁺ lymphocytes: Implications for mechanism of action in multiple sclerosis

Aiden Haghikia, Simon Faissner, Derek Pappas, Bartosz Pula, Denis A. Akkad, Larissa Arning, Sabrina Ruhrmann, Alexander Duscha, Ralf Gold, Sergio E. Baranzini, Sunny Malhotra, Xavier Montalban, Manuel Comabella, Andrew Chan

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

6 Citations (Scopus)

Abstract

© 2014 The Author(s). Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (m) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of m. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

Original language	English
Pages (from-to)	1262-1270
Journal	Multiple Sclerosis
Volume	21
Issue number	10
DOIs	https://doi.org/10.1177/1352458514561909
Publication status	Published - 8 Sep 2015

Keywords

disease-modifying therapy (DMT)
immune cellular energy metabolism
interferon-β
Multiple sclerosis
oxidative phosphorylation
PGC-1α

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Haghikia, A., Faissner, S., Pappas, D., Pula, B., Akkad, D. A., Arning, L., Ruhrmann, S., Duscha, A., Gold, R., Baranzini, S. E., Malhotra, S., Montalban, X., Comabella, M., & Chan, A. (2015). Interferon-beta affects mitochondrial activity in CD4⁺ lymphocytes: Implications for mechanism of action in multiple sclerosis. Multiple Sclerosis, 21(10), 1262-1270. https://doi.org/10.1177/1352458514561909

Haghikia, Aiden ; Faissner, Simon ; Pappas, Derek ; Pula, Bartosz ; Akkad, Denis A. ; Arning, Larissa ; Ruhrmann, Sabrina ; Duscha, Alexander ; Gold, Ralf ; Baranzini, Sergio E. ; Malhotra, Sunny ; Montalban, Xavier ; Comabella, Manuel ; Chan, Andrew. / Interferon-beta affects mitochondrial activity in CD4⁺ lymphocytes: Implications for mechanism of action in multiple sclerosis. In: Multiple Sclerosis. 2015 ; Vol. 21, No. 10. pp. 1262-1270.

@article{ddcbda1f676e44bb9b9c3900b990dacd,

title = "Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis",

abstract = "{\textcopyright} 2014 The Author(s). Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (m) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of m. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.",

keywords = "disease-modifying therapy (DMT), immune cellular energy metabolism, interferon-β, Multiple sclerosis, oxidative phosphorylation, PGC-1α",

author = "Aiden Haghikia and Simon Faissner and Derek Pappas and Bartosz Pula and Akkad, {Denis A.} and Larissa Arning and Sabrina Ruhrmann and Alexander Duscha and Ralf Gold and Baranzini, {Sergio E.} and Sunny Malhotra and Xavier Montalban and Manuel Comabella and Andrew Chan",

year = "2015",

month = sep,

day = "8",

doi = "10.1177/1352458514561909",

language = "English",

volume = "21",

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journal = "Multiple Sclerosis Journal",

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Haghikia, A, Faissner, S, Pappas, D, Pula, B, Akkad, DA, Arning, L, Ruhrmann, S, Duscha, A, Gold, R, Baranzini, SE, Malhotra, S, Montalban, X, Comabella, M & Chan, A 2015, 'Interferon-beta affects mitochondrial activity in CD4⁺ lymphocytes: Implications for mechanism of action in multiple sclerosis', Multiple Sclerosis, vol. 21, no. 10, pp. 1262-1270. https://doi.org/10.1177/1352458514561909

Interferon-beta affects mitochondrial activity in CD4⁺ lymphocytes: Implications for mechanism of action in multiple sclerosis. / Haghikia, Aiden; Faissner, Simon; Pappas, Derek; Pula, Bartosz; Akkad, Denis A.; Arning, Larissa; Ruhrmann, Sabrina; Duscha, Alexander; Gold, Ralf; Baranzini, Sergio E.; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Chan, Andrew.

In: Multiple Sclerosis, Vol. 21, No. 10, 08.09.2015, p. 1262-1270.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis

AU - Haghikia, Aiden

AU - Faissner, Simon

AU - Pappas, Derek

AU - Pula, Bartosz

AU - Akkad, Denis A.

AU - Arning, Larissa

AU - Ruhrmann, Sabrina

AU - Duscha, Alexander

AU - Gold, Ralf

AU - Baranzini, Sergio E.

AU - Malhotra, Sunny

AU - Montalban, Xavier

AU - Comabella, Manuel

AU - Chan, Andrew

PY - 2015/9/8

Y1 - 2015/9/8

N2 - © 2014 The Author(s). Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (m) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of m. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

AB - © 2014 The Author(s). Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (m) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of m. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

KW - disease-modifying therapy (DMT)

KW - immune cellular energy metabolism

KW - interferon-β

KW - Multiple sclerosis

KW - oxidative phosphorylation

KW - PGC-1α

U2 - 10.1177/1352458514561909

DO - 10.1177/1352458514561909

M3 - Article

VL - 21

SP - 1262

EP - 1270

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

SN - 1352-4585

IS - 10

ER -