Identifying and targeting abnormal mitochondrial localization associated with psychoses: Images and Single Cell Profiles

Images and single-cell profiles used for the publication "Identifying and targeting abnormal mitochondrial localization associated with psychoses" by Haghighi and McPhie et al., 2025. Currently preprinted at: https://www.biorxiv.org/cgi/content/short/2025.10.08.676630v1 New therapeutics, working by novel mechanisms, are needed for patients with psychiatric disorders. Cell-based assays to identify candidates could accelerate the process. Here, we imaged peripheral cells (skin fibroblasts) of 178 patients, stained for DNA, actin, and mitochondria. We found mitochondria tend to be farther from the cell border for patients who experience psychosis (including subsets of those with bipolar disorder, schizophrenia, and schizoaffective disorder). We observed a reverse trend, albeit not statistically significant, for patients diagnosed with major depression. Because the mitochondrial dispersion phenotype could be identified by a single metric, we could readily query existing databases of cells stained for their mitochondria and treated with various chemical or genetic perturbations. This virtual screen identified compounds and genes both negatively and positively affecting the mental health condition-associated phenotype, including some known to impact these conditions. Although developing therapeutics with novel mechanisms is an enormous multi-step challenge, this cell-based assay holds promise for virtual and physical screening to identify candidates for psychiatric conditions.