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Abstract：
Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and optic nerve damage. In the current study, we investigate the use of codon-optimized versions of OPA1 isoform 1 and 7 as potential therapeutic interventions in a range of in vitro and in vivo models of mitochondrial dysfunction. We demonstrate that both isoforms perform equally well in ameliorating mitochondrial dysfunction in OPA1 knockout mouse embryonic fibroblast cells but that OPA1 expression levels require tight regulation for optimal benefit. Of note, we demonstrate for the first time that both OPA1 isoform 1 and 7 can be used independently to protect spatial visual function in a murine model of retinal ganglion cell degeneration caused by mitochondrial dysfunction, as well as providing benefit to mitochondrial bioenergetics in DOA patient derived fibroblast cells. These results highlight the potential value of OPA1-based gene therapy interventions.
摘要：
视神经萎缩症1（OPA1）是一种线粒体靶向的GTP酶，在线粒体健康中起着关键作用，突变导致严重的线粒体功能障碍，通常与显性视神经萎缩（DOA）有关，涉及视网膜神经节细胞丢失和视神经损伤的进行性致盲疾病。在目前的研究中,我们研究了OPA1同工型1和7的密码子优化版本在一系列线粒体功能障碍的体外和体内模型中作为潜在治疗干预措施的应用.我们证明，两种同工型在改善OPA1敲除小鼠胚胎成纤维细胞的线粒体功能障碍方面表现相同，但OPA1表达水平需要严格调节以获得最佳益处。值得注意的是，我们首次证明，OPA1亚型1和7可独立用于保护线粒体功能障碍引起的视网膜神经节细胞变性的小鼠模型的空间视觉功能，以及为DOA患者来源的成纤维细胞的线粒体生物能量学提供益处。这些结果突出了基于OPA1的基因治疗干预的潜在价值。
