Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, whose functions in many instances converge with those of OPA1, have been identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.

显性视神经萎缩 (DOA) 是一种遗传性线粒体疾病，会导致视网膜神经节细胞 (RGC) 发生特异性退化，从而影响视觉信息从视网膜到大脑的传输。通常，DOA 在儿童时期开始，并演变为视力不佳或法定失明，影响中央视力，同时保留周边视野。在 20% 的病例中，DOA 表现为综合征性疾病，继发症状影响神经元和肌肉功能。二十年前，我们证明了OPA1的杂合突变是 DOA 最常见的分子原因。从那时起，其他基因的变异，其功能在许多情况下与 OPA1 的功能一致，已被下一代测序识别。OPA1编码导入线粒体并位于内膜和膜间隙的动力蛋白相关 GTP 酶。由三个外显子的可变剪接产生的许多 OPA1 亚型形成构成线粒体嵴的复杂均聚物，并有助于外膜融合，从而塑造整个线粒体网络。此外，OPA1 是氧化磷酸化、维持线粒体基因组、钙稳态和细胞凋亡调节所必需的，因此使 OPA1 成为瑞士军刀线粒体。了解 DOA 病理生理学需要了解 RGC 在 OPA1 功能方面的特性。除了 RGC 将视觉信息从眼睛传递到大脑所需的巨大能量外，这些神经元还具有与其在视网膜中的不同环境相关的独特特征，以及发生在筛板的解剖学转变，这与线粒体生理学的主要适应相平行和形状，在视神经的前层状和后层状部分。三种 DOA 小鼠模型，具有不同的Opa1已经产生突变来研究导致 RGC 变性的内在机制，并且这些突变进一步揭示了与线粒体功能障碍相关的继发性症状，反映了在患者亚组中看到的更严重的综合征表型。对OPA1突变的细胞、小鼠器官和患者血浆的代谢组学分析揭示了与线粒体功能障碍相关的新的意想不到的病理生理机制，并且生物标志物与疾病的严重程度在数量上相关。在这里，我们回顾和综合这些数据，并提出不同的方法来采用可能的治疗方法来满足该疾病未满足的临床需求，并为受影响的 DOA 患者带来希望。