What disease mechanisms contribute to multisystem tissue involvement in dominant optic atrophy due to OPA1 mutations?

常染色体显性视神经萎缩（DOA）影响视神经，引起儿童早期的隐性视力丧失。它是最常见的遗传性视神经疾病，大多数患者携带对正常线粒体功能至关重要的核基因OPA1突变。线粒体是所有人类细胞的基本组成部分，包含自身DNA （MtDNA）的多个拷贝，并形成长分支网络，为细胞的能量需求提供燃料。约20%的OPA1突变患者会发展为更严重的疾病（DOA+），伴有更差的视觉预后和额外的神经系统并发症。发生DOA+的风险是位于GTPase基因区域的错义突变的三倍。使用一系列人体组织样本，我将研究这个特定的突变亚群是否会导致线粒体网络更大的碎片化和更明显的mtDNA损伤，从而加速细胞死亡。我还将探讨通过操纵参与网络融合和裂变的OPA1和其他线粒体蛋白的表达水平来挽救碎片化缺陷的可能性。DOA患者的视力丧失是进行性的，神经功能在以后的生活中发展，为治疗干预提供了明确的机会。

Autosomal dominant optic atrophy (DOA) affects the optic nerve, causing insidious visual loss from early childhood. It is the most common inherited optic nerve disorder and the majority of patients carry mutations in OPA1, a nuclear gene critical for normal mitochondrial function. Mitochondria are essential components of all human cells, containing multiple copies of their own DNA (MtDNA), and forming long branching networks which fuel the cell‘s energy requirements.About 20% of patients with OPA1 mutations will develop a more severe form of the disease (DOA+), associated with a worse visual prognosis and additional neurological complications. The risk of developing DOA+ is three times higher with missense mutations located within the GTPase gene region. Using a range of human tissue samples, I will investigate whether this specific mutational subgroup results in greater fragmentation of the mitochondrial network and more marked mtDNA damage, thus contributing to accelerated cell death. I will also explore the possibility of rescuing the fragmentation defect by manipulating the level of expression of OPA1 and other mitochondrial proteins involved in network fusion and fission. Visual loss in DOA is progressive and the neurological features develop in later life, providing a clear window of opportunity for therapeutic intervention.