Engrailed-1 potentiates mitochondrial transplant neuroprotection in spinal cord ischemia-reperfusion injury

Spinal cord ischemia-reperfusion injury (SCI/RI) triggers severe mitochondrial dysfunction and neuronal death. While mitochondrial transplantation (MT) is a promising strategy, its therapeutic potency remains limited. This study identifies the transcription factor Engrailed-1 (En-1) as a key regulator of mitochondrial homeostasis and a potential enhancer of MT. En-1 expression is significantly downregulated in SCI/RI models, whereas its restoration via hypoxic preconditioning or overexpression markedly improves neuronal survival. Mechanistically, En-1 stabilizes mitochondrial membrane potential, attenuates reactive oxygen species (ROS) production, and inhibits apoptosis by transcriptionally upregulating PDGFC. Mitochondria harvested from En-1-overexpressing cells (OE-En1-Mito) exhibit superior bioenergetic profiles and rapid neuronal uptake compared to unmodified mitochondria. In vitro, OE-En1-Mito increased ATP production and antioxidant activity; in vivo, transplantation preserved neuronal integrity and improved motor recovery in SCI/RI rats. Notably, silencing PDGFC in donor mitochondria abolished these neuroprotective benefits. Thus, En-1-modified MT provides superior neuroprotection for SCI/RI by leveraging the En-1/PDGFC axis.