Mitochondrial Dysfunction in Kidney Transplantation: A Mechanistic Link Between Ischemic Injury and Chronic Allograft Damage

Abstract

Kidney transplantation remains the preferred treatment for end-stage kidney disease, yet ischemia–reperfusion injury continues to compromise early graft recovery and long-term allograft survival. The concept of mitochondrial dysfunction has come to play a key role in the understanding of the relationship between peri-transplant ischemic injury and chronic allograft damage. Warm and cold ischemia leads to impaired oxidative phosphorylation, ATP depletion, calcium imbalance and metabolic disruption that destabilize renal tubular cells and endothelial cells. Excessive generation of ROS, membrane depolarization, permeability transition, defective mitophagy, and activation of apoptosis, necroptosis and ferroptosis are further exacerbated during reperfusion. CGAS–STING activation, activation of the NLRP3 inflammasome, endothelial inflammation, recruitment of leukocytes, and alloimmune responses are also promoted by damaged mitochondria releasing mitochondrial DNA and other damage associated molecular patterns. The lack of mitochondrial homeostasis can perpetuate tubular and endothelial dysfunction, promote maladaptive reparative response, induce fibroblast activation and present a risk of interstitial fibrosis, tubular atrophy, microvascular rarefaction, delayed graft function, and chronic allograft dysfunction. New mitochondrial biomarkers such as circulating and urinary mitochondrial DNA, metabolic signatures and respiratory parameters could help to better evaluate the graft and to better stratify the risk. There are several promising strategies to protect the graft such as those using antioxidants targeted to the mitochondria, metabolic modulators, mitophagy-directed therapies, and machine-perfusion strategies. Targeting mitochondrial dysfunction may therefore provide an integrated strategy to reduce ischemic injury and preserve long-term kidney allograft function.