THE CROSSTALK BETWEEN THE EPIGENOME AND MITOCHONDRIA AS CENTRAL PLAYER IN NEURAL FATE DECISIONS OF THE AXOTOMIZED NEURONS AFTER SPINAL CORD INJURY

Spinal cord injury (SCI) is a devastating condition of the CNS for which no restorative therapies exist. Neuronal death at the primary lesion site and in remote, functionally connected regions contributes to the neurological deficits observed after SCI. In this study, we investigated the crosstalk between mitochondria and the epigenome—termed “mitonuclear communication”—and its role in remote damage in the red nucleus (RN) contralateral to the injury. Using a mouse SCI model, RNA-seq analysis of RN from control and injured mice revealed few differentially expressed genes, with most being upregulated. To gain deeper insight into translational changes, we performed proteomic analysis at 7 and 28 days post-injury. Results showed dramatic proteome remodeling at 7 days, which was attenuated by 28 days after SCI. Integrated pathway analysis identified the histone demethylase KDM5A as a putative upstream regulator of these changes. Immunofluorescence confirmed a global increase of its downstream target H3K4me3 specifically in neurons at 7 days. These findings suggest that bidirectional crosstalk between KDM5A and mitochondria coordinates early responses in the RN after SCI. Overall, our results reveal that supraspinal regions undergo dynamic translational and epigenetic remodeling following SCI, and that KDM5A-mediated mitonuclear communication represents a potential target for interventions aimed at mitigating secondary neuronal damage.
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.