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Vaena S, Chakraborty P, Lee HG, et al. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell Rep. 2021;35(5):109076doi: 10.1016/j.celrep.2021.109076.
Vaena, S., Chakraborty, P., Lee, H. G., Janneh, A. H., Kassir, M. F., Beeson, G., Hedley, Z., Yalcinkaya, A., Sofi, M. H., Li, H., Husby, M. L., Stahelin, R. V., Yu, X. Z., Mehrotra, S., & Ogretmen, B. (2021). Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell reports, 35(5), 109076. https://doi.org/10.1016/j.celrep.2021.109076
Vaena, Silvia, et al. "Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response." Cell reports vol. 35,5 (2021): 109076. doi: https://doi.org/10.1016/j.celrep.2021.109076
Vaena S, Chakraborty P, Lee HG, Janneh AH, Kassir MF, Beeson G, Hedley Z, Yalcinkaya A, Sofi MH, Li H, Husby ML, Stahelin RV, Yu XZ, Mehrotra S, Ogretmen B. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell Rep. 2021 May 04;35(5):109076. doi: 10.1016/j.celrep.2021.109076. PMID: 33951438; PMCID: PMC8127241.
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Cell Rep. 2021 May 04;35(5):109076. doi: 10.1016/j.celrep.2021.109076.

Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response.

Cell reports

Silvia Vaena, Paramita Chakraborty, Han Gyul Lee, Alhaji H Janneh, Mohamed Faisal Kassir, Gyda Beeson, Zachariah Hedley, Ahmet Yalcinkaya, M Hanief Sofi, Hong Li, Monica L Husby, Robert V Stahelin, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen

Affiliations

  1. Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
  2. Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
  3. College of Pharmacy, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
  4. Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
  5. Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Public Health, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
  6. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
  7. Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA. Electronic address: [email protected].

PMID: 33951438 PMCID: PMC8127241 DOI: 10.1016/j.celrep.2021.109076

Abstract

We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: CerS6; PKA; SS SphK2; T cell; aging; immunotherapy; lipid signaling; melanoma; mitophagy; sphingolipids and ceramide

Conflict of interest statement

Declaration of interests B.O. is an inventor on a provisional patent application covering ceramide analogs as therapeutic agents owned by the MUSC Foundation for Research Development. S.M. and B.O. ar

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