Kidney transplantation is inevitably accompanied by ischemia-reperfusion injury in which oxidative stress and endoplasmic reticulum (ER) stress act as tightly interconnected drivers of mitochondrial dysfunction, inflammation, and long-term graft failure. Excessive reactive oxygen species disrupt mitochondrial homeostasis, while unresolved ER stress activates maladaptive unfolded protein response signaling, together shaping tubular cell fate. Although these processes have been extensively studied, their spatial and functional integration remains incompletely understood. Growing evidence indicates that oxidative stress and ER stress converge at mitochondria-associated membranes (MAMs), where calcium signaling, redox regulation, and stress-adaptive networks are integrated. However, the dynamic and context-dependent nature of MAM remodeling remains poorly defined and difficult to investigate using conventional experimental systems. In this review, we propose a MAM-centered framework that integrates cellular stress responses, with a particular focus on ischemia-reperfusion in kidney transplantation. We further highlight therapeutic strategies targeting MAM-associated pathways, including mitochondria-directed antioxidants, ER oxidoreductases and structural and signaling proteins of MAM. In parallel, we summarize emerging kidney organoid platforms as human-relevant translational systems for modeling MAM dynamics under controlled conditions. By integrating mechanistic insights with organoid-based investigations, this review bridges a critical gap between molecular understanding and translational application, and offers a conceptual framework for MAM-targeted strategies aimed at improving graft resilience and long-term transplant outcomes.
Kuang et al. (Fri,) studied this question.