Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response
Silvia G. Vaena, Paramita Chakraborty, Han Gyul Lee, Alhaji H. Janneh, Mohamed Faisal Kassir, Gyda Beeson, Zachariah Hedley, Ahmet Yalçınkaya, M. Hanief Sofi, Hong Li, Monica L. Husby, Robert V. Stahelin, Xue‐Zhong Yu, Shikhar Mehrotra, Besim Öğretmen
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.