Abstract
The transport of mitochondrial proteins, which are encoded by gDNA and synthesized by free ribosomes in the cytosol, to the organelle must be error-free for the proper functioning of mitochondria. It has been shown that abnormal mitochondrial morphology, decreased membrane potential, ATP production, and increased ROS affect mitochondrial protein import. Also, possible target genes of common miRNAs, which are involved in the regulation of secondary mitochondrial damage observed in rare neuromuscular diseases, have been found to be associated with mitochondrial protein import. For this purpose, the relationship between mitochondrial protein import mechanism and mitochondrial damage observed as a common and secondary finding in the etiopathogenesis of DMD, Megaconial CMD, and Ullrich CMD was investigated. As the first step, the pcDNA3/Mito-GFP plasmid containing a mitochondrial targeting signal sequence was transfected into primary myoblasts of the control and patient groups, and a significant decrease in MitoGFP-TOM20 co-localization was observed in all patients. When miR-382-5p, which we directly associate with secondary mitochondrial damage, was co-transfected with pcDNA3/mito-GFP into C2C12 cells, a significant reduction in MitoGFP-TOM20 co-localization was detected compared to the control. As the second step, proteomic analyses were performed by LC-MS/MS after isolation of mitochondria from primary myoblasts. Although the amount of SLC25A4, which acts as an ATP/ADP transporter, decreased in the mitochondrial fraction, it was determined that its expression at the RNA and protein level was preserved in total cells by qRT-PCR and Western Blot. Decreased localization of SLC25A4 in mitochondria in primary myoblasts of patients was confirmed by SLC25A4-TOM20 co-immunofluorescence staining. With this thesis, the potential role of the mitochondrial import mechanism in rare neuromuscular diseases in which secondary mitochondrial damage is seen in the pathogenesis has been elucidated, allowing the identification of common therapeutic targets for new and different disease groups to prevent/reverse organelle damage.
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