Abstract：
In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene. By combining functional and transcriptomic approaches, we investigated the mitochondrial function and identified cellular phenotypes associated with the disease. Our findings revealed that fibroblasts with the OPA1 mutation exhibited a disrupted mitochondrial network and function, leading to altered mitochondrial dynamics and reduced autophagic response. Additionally, we observed a premature senescence phenotype in these cells, suggesting a previously unexplored role of the OPA1 gene in inducing senescence in ADOA plus patients. This study provides novel insights into the mechanisms underlying mitochondrial dysfunction in ADOA plus and highlights the potential importance of senescence in disease progression.
摘要：
在一些线粒体疾病的情况下，线粒体功能障碍中氧化磷酸化（OxPhos）降低的潜在遗传和生物能量原因已广为人知。然而,关于每个基因和突变所涉及的特定细胞结果和因素的知识仍然有限，这导致这些疾病缺乏有效的治疗方法。这项研究的重点是患有常染色体显性视神经萎缩（ADOA）加综合征的患者的成纤维细胞，该综合征在视神经萎缩1（OPA1）基因中具有突变。通过结合功能和转录组学方法，我们研究了线粒体功能并鉴定了与疾病相关的细胞表型.我们的发现表明，OPA1突变的成纤维细胞表现出线粒体网络和功能被破坏，导致线粒体动力学改变和自噬反应减少。此外,我们在这些细胞中观察到了过早衰老的表型，提示OPA1基因在诱导ADOA+患者衰老中的作用。这项研究为ADOA+线粒体功能障碍的潜在机制提供了新的见解，并强调了衰老在疾病进展中的潜在重要性。
