Cx43-mediated mitochondrial transfer from MSCs mitigate oxidative stress-inflammation interplay in IRI-AKI via PGC1a activation

Ischemia Reperfusion Injury-related Acute Kidney Injury (IRI-AKI) is a significant clinical challenge characterized by interrupted blood flow to the kidneys, leading to substantial complications such as prolonged hospital stays, chronic kidney disease, and increased mortality rates. Current management strategies are limited to supportive care, underscoring the need for targeted therapies. This study investigates the potential of Mesenchymal Stromal Cells (MSCs) to transfer functional mitochondria to damaged renal cells via gap junctions, specifically connexin 43 (Cx43), in a clinically relevant surgical model of IRI-AKI. We conducted a time-course analysis to identify critical time points for mitochondrial dysfunction and the optimal therapeutic window for MSC administration, comparing the reno-protective effects of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) in both in vivo and in vitro models. Additionally, we explored the activation of mitochondrial biogenesis and dynamics signaling pathways, particularly PGC1α, to assess the restoration of mitochondrial homeostasis in IRI-AKI, and its potential to disrupt the oxidative stress-inflammation axis, paving the way for precision therapies in treating IRI-AKI.