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

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

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.