Carelli Valerio, La Morgia Chiara, Valentino Maria Lucia, Barboni Piero, Ross-Cisneros Fred N, Sadun Alfredo A
Department of Neurological Sciences, University of Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy.
Biochim Biophys Acta. 2009 May;1787(5):518-28. doi: 10.1016/j.bbabio.2009.02.024. Epub 2009 Mar 5.
Since the early days of mitochondrial medicine, it has been clear that optic atrophy is a very common and sometimes the singular pathological feature in mitochondrial disorders. The first point mutation of mitochondrial DNA (mtDNA) associated with the maternally inherited blinding disorder, Leber's hereditary optic neuropathy (LHON), was recognized in 1988. In 2000, the other blinding disorder, dominant optic atrophy (DOA) Kjer type, was found associated with mutations in the nuclear gene OPA1 that encodes a mitochondrial protein. Besides these two non-syndromic optic neuropathies, optic atrophy is a prominent feature in many other neurodegenerative diseases that are now recognized as due to primary mitochondrial dysfunction. We will consider mtDNA based syndromes such as LHON/dystonia/Mitochondrial Encephalomyopahty Lactic Acidosis Stroke-like (MELAS)/Leigh overlapping syndrome, or nuclear based diseases such as Friedreich ataxia (mutations in FXN gene), deafness-dystonia-optic atrophy (Mohr-Tranebjerg) syndrome (mutations in TIMM8A), complicated hereditary spastic paraplegia (mutations in SPG7), DOA "plus" syndromes (mutations in OPA1), Charcot-Marie-Tooth type 2A (CMT2A) with optic atrophy or hereditary motor and sensory neuropathy type VI (HMSN VI) (mutations in MFN2), and Costeff syndrome and DOA with cataract (mutations in OPA3). Thus, genetic errors in both nuclear and mitochondrial genomes often lead to retinal ganglion cell death, a specific target for mitochondrial mediated neurodegeneration. Many mechanisms have been studied and proposed as the bases for the pathogenesis of mitochondrial optic neuropathies including bioenergetic failure, oxidative stress, glutamate toxicity, abnormal mitochondrial dynamics and axonal transport, and susceptibility to apoptosis.
自线粒体医学早期以来，很明显视神经萎缩是线粒体疾病中非常常见的，有时甚至是唯一的病理特征。与母系遗传的致盲疾病——Leber遗传性视神经病变（LHON）相关的线粒体DNA（mtDNA）的首个点突变于1988年被识别出来。2000年，另一种致盲疾病——显性视神经萎缩（DOA）Kjer型，被发现与编码线粒体蛋白的核基因OPA1中的突变有关。除了这两种非综合征性视神经病变外，视神经萎缩在许多其他现在被认为是由原发性线粒体功能障碍引起的神经退行性疾病中也是一个突出特征。我们将考虑基于mtDNA的综合征，如LHON/肌张力障碍/线粒体脑肌病伴乳酸酸中毒和卒中样发作（MELAS）/Leigh重叠综合征，或基于核基因的疾病，如弗里德赖希共济失调（FXN基因突变）、耳聋-肌张力障碍-视神经萎缩（Mohr-Tranebjerg）综合征（TIMM8A基因突变）、复杂遗传性痉挛性截瘫（SPG7基因突变）、DOA“加”综合征（OPA1基因突变）、伴有视神经萎缩的2A型遗传性运动感觉神经病（CMT2A）或VI型遗传性运动感觉神经病（HMSN VI）（MFN2基因突变），以及科斯特夫综合征和伴有白内障的DOA（OPA3基因突变）。因此，核基因组和线粒体基因组中的遗传错误常常导致视网膜神经节细胞死亡，这是线粒体介导的神经退行性变的一个特定靶点。人们已经研究并提出了许多机制作为线粒体视神经病变发病机制的基础，包括生物能量衰竭、氧化应激、谷氨酸毒性、线粒体动力学和轴突运输异常以及对细胞凋亡的易感性。
