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Mitochondria, colloquially known as the "powerhouses of the cell" are crucial for generating cellular energy through a process known as oxidative phosphorylation (OXPHOS). These minute but mighty organelles are distinct and semi-independent entities, containing their own DNA, which is circular in nature. This DNA has the capacity for replication, transcription, and translation, processes collectively referred to as mitochondrial gene expression. Out of the OXPHOS system's peptides, mitochondria encode for 13, with the remainder being produced in the nucleus and then transported into the mitochondria. The complex system of gene expression within mitochondria relies on an intricate interaction among DNA, RNA, and proteins. However, disruptions in this system have been linked to a variety of diseases, such as diabetes, neurodegenerative disorders, and cancer. RNA-binding proteins (RBPs) are essential in regulating various aspects of RNA's lifecycle, including its synthesis, stability, processing, epitranscriptomic modification, translation, and degradation. Yet, the specifics of how these proteins operate remain partially understood. My doctoral research has been devoted to uncovering new RBPs and elucidating their roles in mitochondrial gene expression. Specifically, in paper 1, I introduced a technique named ‘mt-TRIzol-RBP-Ex’ for the efficient and unbiased enrichment of mitochondrial RBPs from HEK293T cells, leading to the identification and partial characterization of a potential novel RBP, C8orf82, in mitochondrial translation. Subsequent papers focused on other RBPs such as C6orf203 (in paper 2) and GTPBP8 (in paper 3), as well as translation initiation factors (in paper 4), revealing their indispensable roles in mitochondrial post-transcriptional pathways. The depletion of these proteins resulted in significant impacts on translation. This doctoral thesis provides a comprehensive review of current knowledge on mitochondrial RBPs and presents both preliminary and

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10-5 and c.2702T > G [p.V901G], MAF 2.51 × 10-3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10-8), viability (P = 8.9 × 10-7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10-4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10-5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.