期刊
CELL REPORTS
卷 35, 期 5, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109076
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资金
- National Institutes of Health (NIH) [AG069769, CA214461, CA214461-03S1, DE016572, P01 CA203628]
- SmartState Endowment in Lipidomics and Drug Discovery
- NIH [C06 RR015455]
- Hollings Cancer Center Support Grant [P30 CA138313]
- Center of Biomedical Research Excellence (Cobre) in Lipidomics and Pathobiology [P30 GM103339]
- Shared Instrumentation Grant [S10 OD018113]
This study reveals that activated T cells from aging mice accumulate high levels of C14/C16 ceramide in the mitochondria, leading to mitophagy and mitochondrial dysfunction. The aging-dependent mitochondrial ceramide inhibits protein kinase A, causing mitophagy in activated T cells, which impairs the antitumor functions of T cells.
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.
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