Defining the imbalance in mitochondrial and cytosolic translatomes underlying mitochondrial disease
Mitochondrial diseases are a heterogeneous group of disorders, classified into primary and secondary mitochondrial diseases (PMD and SMD). Mitochondria possess their own DNA (mtDNA), which encodes 13 proteins essential for oxidative phosphorylation. The remaining 99% of mitochondrial proteins are encoded by the nuclear genome. Coordination between these genomes is essential for homeostasis and cellular energy production. Mutations in mitochondrial genes can disrupt the coordination of the two genomes and may contribute to mitochondrial disorder pathogenesis. In this project, we explored the impact of disease-causing mutations genes on gene expression dynamics in PMD and SMD. RNA sequencing was performed from patient-derived fibroblast cells with PMD caused by mutations in MTFMT, MT-ATPase, and SURF1, and SMD caused by mutations in DNM1 and ATP6V1A. We generated a pipeline to map the reads to the human transcriptome and quantify read counts for gene expression analysis. We utilized DESeq2 to conduct differential expression analyses and prioritized mitochondrial genes which were extracted from MitoCarta3. Additionally, Gene Set Enrichment Analysis (GSEA) was performed to investigate the involvement of specific signaling pathways and biological processes. This comprehensive approach enabled us to decipher complex gene expression changes and their functional implications in the context of PMD and SMD mutations.
