YOMP: Yeast model and omics studies to deepen the knowledge about the mitochondrial metallopeptidase PITRM1 in health and disease
ProgettoThe YOMP project (Yeast model and omics studies to deepen the knowledge about the mitochondrial metallopeptidase PITRM1 in health and disease) aimed to investigate the role of the mitochondrial metallopeptidase PITRM1 in mitochondrial proteostasis and in the pathogenic mechanisms underlying both rare mitochondrial disorders and neurodegenerative diseases. To achieve this goal, the project combined genetically tractable yeast models (Saccharomyces cerevisiae), multi-omics approaches (transcriptomics and proteomics), and validation studies in patient-derived fibroblasts carrying PITRM1 variants.
The main objectives were: (i) the functional characterization of pathogenic PITRM1 variants associated with SCAR30 (spinocerebellar ataxia, cognitive decline and psychotic episodes) and of variants potentially linked to Alzheimer’s disease; (ii) the identification of molecular and cellular alterations caused by PITRM1 dysfunction; (iii) the investigation of mitochondrial stress responses and mitochondria–cytosol–nucleus crosstalk involved in disease mechanisms; and (iv) the integration of multi-omics datasets to identify conserved molecular signatures and disease-related pathways across experimental models and human cells.
The expected outcomes included a deeper understanding of the functional consequences of PITRM1 variants, the identification of dysregulated biological pathways associated with mitochondrial dysfunction, the characterization of cellular stress responses triggered by impaired PITRM1 activity, and the generation of integrated datasets useful for elucidating the molecular basis of PITRM1-related diseases.
The project successfully achieved its planned objectives. Yeast models expressing pathogenic PITRM1/CYM1 variants were generated and characterized, revealing respiratory defects, impaired mitochondrial proteostasis, and activation of adaptive responses such as the mitochondrial unfolded protein response (mtUPR) and mitophagy. Comprehensive transcriptomic and proteomic analyses performed in both yeast and patient-derived fibroblasts identified alterations in mitochondrial metabolism, protein folding, membrane biosynthesis, and catabolic processes. The integration of multi-omics datasets enabled the identification of conserved molecular signatures and mechanistic pathways associated with PITRM1 dysfunction. Overall, the project generated an extensive and valuable resource of experimental data, significantly advanced the understanding of PITRM1-related pathophysiology, and established a strong foundation for future research activities and the preparation of multiple peer-reviewed scientific publications.
The main objectives were: (i) the functional characterization of pathogenic PITRM1 variants associated with SCAR30 (spinocerebellar ataxia, cognitive decline and psychotic episodes) and of variants potentially linked to Alzheimer’s disease; (ii) the identification of molecular and cellular alterations caused by PITRM1 dysfunction; (iii) the investigation of mitochondrial stress responses and mitochondria–cytosol–nucleus crosstalk involved in disease mechanisms; and (iv) the integration of multi-omics datasets to identify conserved molecular signatures and disease-related pathways across experimental models and human cells.
The expected outcomes included a deeper understanding of the functional consequences of PITRM1 variants, the identification of dysregulated biological pathways associated with mitochondrial dysfunction, the characterization of cellular stress responses triggered by impaired PITRM1 activity, and the generation of integrated datasets useful for elucidating the molecular basis of PITRM1-related diseases.
The project successfully achieved its planned objectives. Yeast models expressing pathogenic PITRM1/CYM1 variants were generated and characterized, revealing respiratory defects, impaired mitochondrial proteostasis, and activation of adaptive responses such as the mitochondrial unfolded protein response (mtUPR) and mitophagy. Comprehensive transcriptomic and proteomic analyses performed in both yeast and patient-derived fibroblasts identified alterations in mitochondrial metabolism, protein folding, membrane biosynthesis, and catabolic processes. The integration of multi-omics datasets enabled the identification of conserved molecular signatures and mechanistic pathways associated with PITRM1 dysfunction. Overall, the project generated an extensive and valuable resource of experimental data, significantly advanced the understanding of PITRM1-related pathophysiology, and established a strong foundation for future research activities and the preparation of multiple peer-reviewed scientific publications.