Connexin 43-dependent mesenchymal stem cell mitochondrial transfer activates PGC1α disrupting oxidative-inflammation axis in ischemia-reperfusion injury.

Ischemia-Reperfusion Injury-related Acute Kidney Injury (IRI-AKI) is a significant clinical challenge. Despite extensive research into the underlying mechanism for IRI-AKI, the development of effective therapeutic interventions remains challenging due to self-perpetuating positive-feedback loops between oxidative stress and inflammation pathways. Mitochondrial dysfunction has been acknowledged as a significant player in the early stages of IRI in causing cellular damage. However, antioxidant therapy has only yielded modest improvements in outcomes. Interestingly, Mesenchymal Stem/Stromal Cells (MSCs) have shown potential in the treatment of AKI through their anti-inflammatory properties, though their ability to disrupt the oxidative stress-inflammation axis remains incompletely understood. In a clinically relevant surgical model of IRI-AKI, we investigated precision delivery of MSCs directly into the kidney, via its arterial blood supply, to ensure spatial in vivo coupling of these cells with injured renal cells. Here, we observed that MSCs, specifically BM-MSCs, mitigated mitochondrial dysfunction during the early stages of IRI-AKI, leading to reduced inflammation, preventing cellular injury and recovery of renal function. Mechanistic studies demonstrated the importance of Connexin 43 (Cx43)-mediated gap junctions in facilitating mitochondrial transfer from MSCs to damaged renal epithelial cells, resulting in activation of PGC1α signaling, a reduction in mitochondrial reactive oxygen species (ROS), and promotion of mitogenesis. These findings highlight the mechanism by which spatially coupled MSCs can restore cellular mitochondrial homeostasis by disrupting the oxidative stress-inflammation axis and paving the way for the development of disease etiology-based therapeutics for treating IRI-AKI.