Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response
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
Silvia Vaena
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
Paramita Chakraborty
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
Han Gyul Lee
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
Alhaji H. Janneh
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
Mohamed Faisal Kassir
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
Gyda Beeson
College of Pharmacy, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Zachariah Hedley
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
Ahmet Yalcinkaya
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
M. Hanief Sofi
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
Hong Li
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
Monica L. Husby
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Robert V. Stahelin
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Xue-Zhong Yu
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
Shikhar Mehrotra
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
Besim Ogretmen
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; Corresponding author
Summary: 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.
