Yu Wai Man C Y, Chinnery P F, Griffiths P G
Department of Neurology, The Medical School, University of Newcastle upon Tyne, UK.
Med Hypotheses. 2005;65(6):1038-42. doi: 10.1016/j.mehy.2004.10.021. Epub 2005 Aug 10.
Optic neuropathies such as Leber's hereditary optic neuropathy, dominant optic atrophy and toxic amblyopia are an important cause of irreversible visual failure. Although they are associated with a defect of mitochondrial energy production, their pathogenesis is poorly understood. A common feature to all these disorders is relatively selective degeneration of the papillomacular bundle of retinal ganglion cells resulting central or caecocentral visual field defects. The striking similarity in the pattern of clinical involvement seen with these disparate disorders suggests a common pathway in their aetiology. The existing hypothesis that the optic nerve head has higher energy demands than other tissues making it uniquely dependent on oxidative phosporylation is not satisfactory. First, other ocular tissues such as photoreceptors, which are more dependent on oxidative phosporylation are not affected. Second, other mitochondrial disorders, which have a greater impact on mitochondrial energy function, do not affect the optic nerve. The optic nerve head has certain unique ultra structural features. Ganglion cell axons exit the eye through a perforated collagen plate, the lamina cribrosa. There is a sharp discontinuity in the density of mitochondria at the optic nerve head, with a very high concentration in the prelaminar nerve fibre layer and low concentration behind the lamina. This has previously been attributed to a mechanical hold up of axoplasmic flow, which has itself been proposed as a factor in the pathogenesis of a number of optic neuropathies. More recent evidence shows that mitochondrial distribution reflects the different energy requirements of the unmyelinated prelaminar axons in comparison to the myelinated retrolaminar axons. The heterogeous distribution of mitochondria is actively maintained to support conduction through the optic nerve head. We propose that factors that disrupt the heterogeneous distribution of mitochondria can result in ganglion cell death. Evidence for this comes from studies of cultured cells with the dominant optic atrophy mutation in which mitochondrial distribution is altered and from some forms of hereditary spastic paraparesis which are associated with optic atrophy. The responsible mutations do not affect ATP production until late in the disease but do affect mitochondrial arrangement, again showing that mitochondrial distribution as well as energy production by individual mitochondria may be important in the pathogenesis of ganglion cell death. Greater understanding of the factors localising mitochondria within the ganglion cell axon in particular the interaction with cytoskeleton is required to formulate new treatments. Boosting energy production alone may not be an effective treatment.
视神经病变，如莱伯遗传性视神经病变、显性遗传性视神经萎缩和中毒性弱视，是不可逆视力丧失的重要原因。尽管它们与线粒体能量产生缺陷有关，但其发病机制仍知之甚少。所有这些疾病的一个共同特征是视网膜神经节细胞的乳头黄斑束相对选择性变性，导致中心或中心暗点视野缺损。这些不同疾病在临床受累模式上的显著相似性表明它们的病因有共同途径。现有的假说认为视神经乳头比其他组织有更高的能量需求，使其独特地依赖于氧化磷酸化，但这并不令人满意。首先，其他更依赖氧化磷酸化的眼组织，如光感受器，并未受到影响。其次，其他对线粒体能量功能影响更大的线粒体疾病，并未影响视神经。视神经乳头具有某些独特的超微结构特征。神经节细胞轴突通过一个穿孔的胶原板——筛板离开眼球。视神经乳头处线粒体密度存在明显的不连续性，在板前神经纤维层浓度非常高，而在筛板后浓度低。这以前被归因于轴浆流的机械阻滞，而轴浆流本身被认为是一些视神经病变发病机制中的一个因素。最近的证据表明，与有髓鞘的板后轴突相比，线粒体分布反映了无髓鞘的板前轴突不同的能量需求。线粒体的异质分布是积极维持的，以支持通过视神经乳头的传导。我们提出，破坏线粒体异质分布的因素可导致神经节细胞死亡。这一观点的证据来自对具有显性遗传性视神经萎缩突变的培养细胞的研究，其中线粒体分布发生改变，以及来自一些与视神经萎缩相关的遗传性痉挛性截瘫形式。相关突变直到疾病后期才影响ATP的产生，但确实影响线粒体排列，再次表明线粒体分布以及单个线粒体的能量产生在神经节细胞死亡的发病机制中可能很重要。需要更深入了解在神经节细胞轴突内定位线粒体的因素，特别是与细胞骨架的相互作用，以制定新的治疗方法。仅提高能量产生可能不是一种有效的治疗方法。
