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 there are no restorative therapies. Neuronal death at the primary lesion site and in remote regions that are functionally connected to it is one of the major contributors to neurological deficits induced by SCI. In this study we examined the crosstalk between mitochondria and the epigenome, defined as “mitonuclear communication” and its contribution to the remote damage-induced by SCI in the red nucleus (RN) contralateral to the injury site. Using a mouse model of SCI, we performed RNA-seq analysis on RN isolated from control and SCI mice. Downstream pathway analysis revealed that the number of differentially expressed genes (DEGs) in RN was very low and most of them were upregulated, rather than downregulated. To get in-depth insight into the translational response activated by SCI, we performed proteomic analysis on RN isolated from control and SCI mice at 7 and 28 days after injury. Our results showed that the proteome of the RN suffers dramatic changes 7 days after SCI, but thistranslational response is tampered at 28 days. Integrated pathway analysis, points out to the histone demethylase KDM5A as the putative upstream regulator of the observed phenotype. Consistent with these data, immunofluorescence experiments showed a global increase of its downstream target H3K4me3 specifically in the neuronal compartment 7 days after injury. These data suggest that a functional–bi-directional–crosstalk between KDM5A and the mitochondria might coordinate the initial responses activated in the RN after SCI.