Introduction: Metabolic plasticity and mitochondrial bioenergetic homeostasis are altered due to a organ ischemia. However, the impact of the alloimmune response on the allograft is not known. The goal of our studies is to establish if bioenergetic dysfunction is linked to metabolic reprogramming of kidney during rejection.

Methods: Kidneys from C57BL/6 were transplanted into MHC-incompatible Balb/c mice (allograft). Kidneys from C57BL/6 were transplanted into their litter-mates as isograft controls. No immunosuppression was given as these grafts have prolonged survival and ongoing cellular rejection. Major mitochondrial electron transport chain (ETC) complexes and metabolic regulators, including AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR) and Hypoxia-inducible factor 1-alpha (HIF-1α), were determined in whole kidney lysates. Western blot analysis also includes regulatory components of mitochondrial biogenesis and tissue remodeling.

Results: Significant loss of mitochondrial ETC complexes was observed in kidney allografts, compared to isografts in the first week post- transplant. Such loss of mitochondrial complexes was accompanied by activation of several metabolic switches involved in reprogramming toward glycolytic metabolism, as evidenced by increased activity of mTOR and HIF-1α in allografts versus isografts. Notably, AMPK activation in allografts suggests that a subset of cells experienced significant and prolonged bioenergetic stress. Importantly, while reduced amounts of mitochondrial ETC complexes persisted in allografts for several weeks, isografts show a remarkable recovery of ETC complexes, similar to the levels observed in naïve kidneys.

Conclusions: Our studies indicate that loss of bioenergetic homeostasis is related to mitochondrial dysfunction and accompanied with metabolic reprogramming in rejecting allografts. Importantly, isograft shows time-dependent recovery of mitochondrial components, dissipation of mTOR and HIF-1α, normalization bioenergetic sensor and metabolic regulator AMPK. Targeting this pathway may ameliorate the kidney injury associated with rejection.

CITATION INFORMATION: Zmijewska A., Zmijewski J., Chen J., Mannon R. Kidney Transplant Rejection is Associated with Robust and Prolonged Bioenergetic Reprogramming and Metabolic Maladaptation Am J Transplant. 2017;17 (suppl 3).

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