PHARMACOLOGICAL TARGETING OF THE MITO-NUCLEAR AXIS AS A KEY REGULATOR OF MOTOR FUNCTION, NEURONAL REORGANIZATION AND BIOENERGETICS AFTER SPINAL CORD INJURY

Spinal cord injury (SCI) triggers widespread molecular and functional alterations in supraspinal neurons that severely limit neuronal reorganization and motor recovery. The epigenetic demethylase KDM5A has emerged as a pivotal regulator of mito-nuclear communication, integrating mitochondrial metabolic state with nuclear gene expression programs essential for neuronal survival and plasticity. Here, we investigated whether pharmacological modulation of the mito-nuclear axis can induce neuronal reorganization, restore neuronal bioenergetics and improve motor function after SCI.
Pharmacological inhibition of KDM5A following SCI induced a robust increase in H3K4me3 levels in axotomized neurons. In parallel, modulation of mitochondrial metabolites through succinic acid supplementation altered KDM5A activity and induced the same epigenetic remodeling. These interventions modulate mitochondrial function, ATP production efficiency, and the bioenergetic failure observed after SCI.
At the cellular level, pharmacological targeting of the mito-nuclear axis modulates neuronal survival and axonal reorganization. Importantly, these molecular and cellular changes translated into significant functional effects. Treated animals exhibited changes in motor function, indicating a plousible recovery.
Together, these findings identify KDM5A as a central regulator of neuronal reorganization and mitochondrial function after SCI and demonstrate that pharmacological targeting of the mito-nuclear axis yields meaningful improvements in motor strength and coordination. This work provides compelling evidence that epigenetic–metabolic interventions represent a promising therapeutic strategy to enhance functional recovery following SCI.
Project titled “The crosstalk between the epigenome and mitochondria as a novel therapeutic target to counteract remote degeneration induced by spinal cord injury” (PNRR-MCNT2-2023-12377641; CUP:C53C23001110007) funded by the Italian Ministry of Health under the European Union-NextGenerationEU.