![]() ![]() 9 Deleted mtDNA molecules can be maternally inherited or acquired somatically, probably due to random replication errors, but they are most often due to mutations in nuclear genes encoding proteins needed for mtDNA maintenance. ![]() In addition, mtDNA also encodes 22 transfer RNAs and 2 ribosomal RNAs, which are essential for translating the 13 messenger RNAs into protein subunits by the mitochondrial ribosomes. 7, 8 These respiratory chain complexes are assembled from a large number of subunits, 13 of which are encoded on mitochondrial DNA (mtDNA), present in thousands of copies in all cells, whereas the rest is encoded on nuclear DNA. 7, 8 ATP generation is carried out by the respiratory chain complexes I–IV and ATP synthase (complex V) that are embedded within the inner mitochondrial membrane. Mitochondria are highly dynamic organelles that are involved in various cellular processes, including ATP generation, calcium buffering, signaling, and apoptosis, but also in intermediary metabolism and synthesis of cellular building blocks. 5, 6 On the one hand, these unique features enable EOMs to mediate a wide range of sophisticated eye movements with very different speeds, but on the other hand, obviously confer differential vulnerability to neuromuscular diseases, including mitochondrial myopathies, for which CPEO is often an early manifestation. 5, 6 Moreover, individual EOM fibers can also co-express several MyHC isoforms along their length. 1 – 4 Besides having fibers that express the typical slow I, fast IIA, and fast IIB myosin heavy chain (MyHC) isoforms observed in limb and trunk muscles, adult EOMs also have fibers that express embryonic MyHC (MyHC-emb), neonatal (MyHC-neo), slow-tonic MyHC, and EOM-specific isoforms (MyHC-eoms). Compared to these, EOMs are loosely packed with unusually high amounts of connective tissue, have a higher mitochondrial content in general, are more vascularized, and have higher calcium handling capacities, reflecting their high metabolic needs. It is caused by slowly progressive paralysis of the extra ocular muscles (EOMs), which are structurally, functionally, and biochemically distinct from other skeletal muscles in the body. Our results point to the existence of fiber type IIB-intrinsic factors and/or molecular mechanisms that predispose them to increased generation, clonal expansion, and detrimental effects of mtDNA deletions.Ĭhronic progressive external ophthalmoplegia (CPEO) is a disorder typically leading to bilateral ptosis and limitation of eye movements. We also show that EOMs of mutant mice display histopathological abnormalities, including altered fiber type composition, increased fibrosis, ragged red fibers, and infiltration of mononucleated nonmuscle cells. Collectively, these results demonstrate a selective vulnerability of type IIB fibers to mitochondrial DNA (mtDNA) deletions in EOMs and retractor bulbi muscle. Furthermore, the proportion of COX − fibers in the type IIB-rich retractor bulbi muscle was > 2-fold higher compared to the M. A significant proportion of these COX − fibers were of the fast-twitch, glycolytic type IIB (> 50% and > 35% total COX − fibers at 12 and 24 months, respectively), whereas embryonic myosin heavy chain-expressing fibers were almost completely spared. The mean average of COX deficient fibers (COX −) in the recti muscles of mutant mice was 1.04 ± 0.52% at 12 months and increased with age (7.01 ± 1.53% at 24 months). The purpose of this study was to gain insights on the pathogenesis of chronic progressive external ophthalmoplegia, thus we investigated the vulnerability of five extra ocular muscles (EOMs) fiber types to pathogenic mitochondrial DNA deletions in a mouse model expressing a mutated mitochondrial helicase TWINKLE.Ĭonsecutive pairs of EOM sections were analyzed by cytochrome C oxidase (COX)/succinate dehydrogenase (SDH) assay and fiber type specific immunohistochemistry (type I, IIA, IIB, embryonic, and EOM-specific staining). ![]()
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