Xhuti Donald, Chiarot Alessandra, Minhas Mahek, Tobia Samantha, de Maat Nicoletta, Manta Katherine, Ng Sean Y, Tarnopolsky Mark A, Nederveen Joshua P
Department of Pediatrics, McMaster University Medical Centre, 1200 Main Street West, Hamilton, ON L8S 3Z5, Canada.
Department of Kinesiology, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.
Hum Mol Genet. 2025 Aug 29. doi: 10.1093/hmg/ddaf125.
Leber's hereditary optic neuropathy (LHON) is characterized by painless and rapidly progressive central vision loss, caused by various mutations in mitochondrial DNA, leading to a high genetic and phenotypic heterogeneity. Currently, the only approved therapy is idebenone, a CoQ10 synthetic analogue, that improved visual acuity in some LHON patients; however, results are highly variable due its dependency on functional NAD(P)H oxidoreductase I (NQO1) protein levels, thus limiting broader applicability. Targeting the biochemical respiratory chain defect and mitigating reactive oxygen species emission using alternative treatments which act independent of NQO1 protein content, represent a promising therapeutic strategy for all LHON patients. Here, we first characterized mitochondrial biology of three distinct LHON mutations in patient-derived fibroblasts and evaluated the effects of a nutraceutical combination treatment in addressing these shared pathophysiological mechanisms. We identified a range of mitochondrial characteristics common among various LHON mutations, including higher ROS levels, altered autophagy programming, and reduced mitochondrial bioenergetics. Repeated antioxidant and creatine-based treatment (ACT) conferred a favorable stress-resistant phenotype in LHON cells, which was similar to, and in some cases superior to, the effects observed with idebenone treatment, irrespective of NQO1 protein expression. This phenotype was associated with enhanced mitochondrial biology, as evidenced by reduced reactive oxygen species levels, increased cellular respiration, and correction of autophagic flux. Overall, our findings reveal both common and divergent mitochondrial phenotypes among LHON-related mutations and highlight the potential of accessible multi-ingredient nutraceutical interventions that could benefit all LHON patients.
Leber遗传性视神经病变（LHON）的特征是无痛且快速进展的中心视力丧失，由线粒体DNA中的各种突变引起，导致高度的遗传和表型异质性。目前，唯一获批的治疗方法是艾地苯醌，一种辅酶Q10合成类似物，它在一些LHON患者中提高了视力；然而，由于其对功能性NAD(P)H氧化还原酶I（NQO1）蛋白水平的依赖性，结果差异很大，从而限制了其更广泛的适用性。针对生化呼吸链缺陷并使用独立于NQO1蛋白含量起作用的替代疗法减轻活性氧的释放，是所有LHON患者一种有前景的治疗策略。在这里，我们首先对患者来源的成纤维细胞中三种不同的LHON突变的线粒体生物学特性进行了表征，并评估了一种营养补充剂联合治疗对解决这些共同病理生理机制的效果。我们确定了各种LHON突变共有的一系列线粒体特征，包括较高的活性氧水平、自噬程序改变和线粒体生物能量学降低。重复进行抗氧化剂和基于肌酸的治疗（ACT）在LHON细胞中赋予了一种有利的抗应激表型，无论NQO1蛋白表达如何，这种表型与艾地苯醌治疗所观察到的效果相似，在某些情况下甚至更优。这种表型与线粒体生物学的增强有关，表现为活性氧水平降低、细胞呼吸增加和自噬通量的纠正。总体而言，我们的研究结果揭示了LHON相关突变中常见和不同的线粒体表型，并突出了可及的多成分营养补充剂干预措施对所有LHON患者有益的潜力。
