Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection

Abstract

Transplantation is invariably associated with programmed cell death including apoptosis and necrosis, resulting in delayed graft function and organ rejection. We have demonstrated the contribution of necroptosis to mouse microvascular endothelial cell (MVEC) death and transplant rejection. Organ injury results in the opening of mitochondrial permeability transition pores (mPTPs), which can trigger apoptotic molecules release that ultimately results in cell death. The effect of mPTPs in the necroptotic pathway remains controversial; importantly, their role in transplant rejection is not clear. In this study, tumor necrosis factor-α triggered MVECs to undergo receptor-interacting protein kinase family (RIPK1/3)-dependent necroptosis. Interestingly, inhibition of mPTP opening could also inhibit necroptotic cell death. Cyclophilin-D (Cyp-D) is a key regulator of the mPTPs. Both inhibition and deficiency of Cyp-D protected MVECs from necroptosis (n = 3, P < .00001). Additionally, inhibition of Cyp-D attenuated RIPK3-downstream mixed-lineage kinase domain-like protein phosphorylation. In vivo, Cyp-D-deficient cardiac grafts showed prolonged survival in allogeneic BALB/c mice posttransplant compared with wild-type grafts (n = 7, P < .0001). Our study results suggest that the mPTPs may be important mechanistic mediators of necroptosis in cardiac grafts. There is therapeutic potential in targeting cell death via inhibition of the mPTP-regulating molecule Cyp-D to prevent cardiac graft rejection.

Circulating mitochondrial genes detect acute cardiac allograft rejection: Role of the mitochondrial calcium uniporter complex

“…In addition, we found a significant downregulation of the transforming growth factor beta regulator 4 ( TBRG4 ) under rejection conditions, which is known to promote apoptosis in knockdown experiments 36 . Our results are in concordance with those of previously published studies, supporting the idea that transplantation is associated with programmed cell death including apoptosis, resulting in delayed graft function and organ rejection 37‐39 …”

Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI

“…Indeed, a recent heart transplant study reported MLKL phosphorylation and necroptosis downstream of PPIF activation. 38 Although dual deficiency of PPIF or MLKL elicited the most potent protective effect on tubular injury, the combinations of two cell death inhibitors with doubtful specificities did not. These data do not exclude independent roles of the both pathways in acute oxalosis, but are consistent with a significant interference of both pathways in crystal cytotoxicity.…”

Toll-like receptor 3 is an endogenous sensor of cell death and a potential target for induction of long-term cardiac transplant survival

“…62,63 We have shown that increased level of Treg cell in lymphoid organ and in the graft correlated with long-term mouse graft survival posttransplant. 17,[64][65][66][67] Necroptosis results in the release of danger molecules from cells as being demonstrated by us and others. 2,[14][15][16] Danger molecules not only participate in graft rejection, 2 they may also provoke inflammation and block tolerance induction via the inhibition of Treg cells.…”

“…In murine transplantation studies, we showed that cells and grafts release HMGB1 under necroptosis. [14][15][16][17] Others have reported that HMGB1 may interact with TLR4 to worsen murine transplant injury or rejection. 5,47,48 However, the roles of other damaging molecules and their receptors in transplant AJT rejection have not been well defined.…”