Analyses of single-cell and bulk RNA sequencing combined with machine learning reveal the expression patterns of disrupted mitophagy in schizophrenia.

Background: Mitochondrial dysfunction is an important factor in the pathogenesis of schizophrenia. However, the relationship between mitophagy and schizophrenia remains to be elucidated. Methods: Single-cell RNA sequencing datasets of peripheral blood and brain organoids from SCZ patients and healthy controls were retrieved. Mitophagy-related genes that were differentially expressed between the two groups were screened. The diagnostic model based on key mitophagy genes was constructed using two machine learning methods, and the relationship between mitophagy and immune cells was analyzed. Single-cell RNA sequencing data of brain organoids was used to calculate the mitophagy score (Mitoscore). Results: We found 7 key mitophagy genes to construct a diagnostic model. The mitophagy genes were related to the infiltration of neutrophils, activated dendritic cells, resting NK cells, regulatory T cells, resting memory T cells, and CD8 T cells. In addition, we identified 12 cell clusters based on the Mitoscore, and the most abundant neurons were further divided into three subgroups. Results at the single-cell level showed that Mitohigh_Neuron established a novel interaction with endothelial cells via SPP1 signaling pathway, suggesting their distinct roles in SCZ pathogenesis. Conclusion: We identified a mitophagy signature for schizophrenia that provides new insights into disease pathogenesis and new possibilities for its diagnosis and treatment.