Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, 3002 Victoria, Australia; Ophthalmology, University of Melbourne, Department of Surgery, Parkville 3010 Victoria, Australia.
School of Life and Environmental Sciences, Deakin University, Geelong, Australia.
Mitochondrion. 2020 Sep;54:113-121. doi: 10.1016/j.mito.2020.07.003. Epub 2020 Jul 18.
Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables unaffected carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G > A lymphoblasts and primary fibroblasts from both unaffected carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in cells from unaffected carrier and affected patients, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells under basal conditions, our results indicate that cells from affected patients suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in unaffected carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.
Leber 遗传性视神经病变（LHON）是最常见的原发性线粒体疾病之一。它是由线粒体 DNA（mtDNA）基因中的点突变引起的，在某些情况下，它会导致不可逆转的视力丧失，主要发生在年轻男性身上。目前尚不清楚为什么 LHON 突变仅影响某些携带者，以及生物能量补偿是否使未受影响的携带者能够克服线粒体损伤并保持细胞功能。在这里，我们使用仅男性、年龄匹配的 m.11778G>A 淋巴母细胞和未受影响的携带者和受影响个体的原代成纤维细胞进行了生物能量代谢测定和 RNA 测序，以解决这个问题。我们的工作表明，LHON 外周细胞中的 OXPHOS 生物能量补偿并不能解释疾病表型。我们表明，尽管通过 RNA 测序检测到受影响细胞中的糖酵解等代谢途径的转录下调，但未受影响的携带者和受影响患者的细胞中复合物 I 损伤相似。虽然我们在基础条件下未在携带者细胞中检测到 OXPHOS 生物能量补偿，但我们的结果表明，与未受代谢挑战影响的携带者细胞相比，受影响患者的细胞在代谢挑战下会遭受生长受损，而携带者细胞不受代谢挑战的影响。如果在视网膜神经节细胞中得到重现，未受影响的携带者对代谢挑战的敏感性降低可能有助于在面对线粒体复合物 I 生物能量缺陷时保持代谢稳态。
