Abstract
Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by the progressive degeneration of photoreceptor and retinal pigment epithelial (RPE) cells, ultimately leading to significant vision loss. While the pathogenesis of RP is associated with mitochondrial dysfunction and immune-inflammatory responses, the specific interplay between disrupted mitochondrial gene expression and immune cell infiltration remains inadequately understood. While gene therapy has been approved for a subset of RP patients with monogenic mutations such as RPE65-associated RP, it has notable limitations beyond high costs: it only targets single-gene defects and fails to reverse advanced retinal degeneration that has already damaged photoreceptors. Thus, a robust understanding of these relationships could unveil novel therapeutic strategies and mechanistic insights into RP. In this study, we employed a rat model of RP to elucidate the interconnections between mitochondrial and immune responses. We utilized RNA sequencing to analyze retinal transcriptomes, focusing on identifying differentially expressed genes (DEGs) linked to mitochondrial function and immune dynamics. Additionally, we performed immune profiling to investigate the composition and alterations of infiltrating immune cell types within the RP retina. Our transcriptomic analysis revealed a plethora of DEGs significantly enriched in mitochondrial and immune pathways. Notably, we identified 280 mitochondrial-related DEGs, among which 10 hub genes (such as Uqcrh and Cox5b) demonstrated critical roles in oxidative phosphorylation and correlated with functional declines in vision. Immune profiling highlighted a pronounced inflammatory shift, characterized by elevated neutrophils and γδ T cells, alongside diminished regulatory T cells and resting natural killer (NK) cells. Further analysis established significant correlations between the ratios of these immune cell types and the expression levels of mitochondrial hub genes. Transcriptional profiling reveals co-occurring alterations in mitochondrial gene expression and immune cell infiltration in RP, with statistical correlations suggesting potential interactions between these two processes, though the direction and mechanism of this interaction require further functional validation. The identification of mitochondrial hub genes and their association with immune cell dynamics not only deepens our understanding of RP but also sets the stage for developing novel therapeutic approaches aimed at mitigating the disruptive effects of these pathways in RP.