Optic neuropathies – Importance of spatial distribution of mitochondria as well as function

https://doi.org/10.1016/j.mehy.2004.10.021Get rights and content

Summary

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.

Section snippets

Unique structural features of the retinal ganglion cells

At the optic nerve head, about 1.2 million unmyelinated RGC axons exit the eye through an opening in the sclera approximately 1.5 mm across. In doing so, they pass though a perforated collagen plate, the lamina cribrosa, before becoming myelinated (Fig. 1). Histological, histochemical and immunocytochemical techniques have shown that the mitochondrial density is high in the prelaminar region but strikingly low in the postlaminar section [1], [2], [3], [4]. This sharp mitochondrial gradient has

Maintenance of this sharp mitochondrial gradient by axonal transport and recruitment

After biogenesis in the soma of the RGCs, mitochondria are transported down the axons to the synaptic terminals. All along the axons, they undergo saltatory, bi-directional movements with the motor proteins kinesin and dynein supporting the anterograde and retrograde transport, respectively [10]. Efficient axonal transport of mitochondria is dependent on two main factors: their own energy production, as axonal transport is ATP-dependent [11], and cytoskeletal–mitochondrial interactions because

The hypothesis

Our hypothesis is that the sharp mitochondrial gradient at the optic nerve head, which is actively maintained by mitochondrial axonal transport and recruitment, is a normal physiological phenomenon that is fundamental for the healthy function of the optic nerve, and any disruption of this gradient constitutes the first step of a final common pathway leading to retinal ganglion cell death.

Not just an ATP deficiency problem

Photoreceptors have higher oxidative demands than RGCs but are spared in optic neuropathies [15]. Although photoreceptors have a high mitochondrial density, they differ from RGCs in not possessing a discontinuous distribution of mitochondria. There are also some disorders that do not involve ATP deficiencies per se but cause optic neuropathies by disrupting the cytoskeletal–mitochondrial interactions and thus the axonal mitochondrial distribution. Dominant optic atrophy (DOA) is caused by

First step of a final common pathway

Factors that disrupt the sharp mitochondrial gradient at the lamina will initiate a vicious cycle of events as mitochondrial axonal transport that serves to maintain the mitochondrial gradient, is an energy dependent process and will thus itself be affected by lower numbers of mitochondria (Fig. 1). The end-result would be profound energy depletion and the increased production of toxic free radicals in the RGCs. This would in turn cause mitochondria to switch on apoptotic cell death by the

Testing the hypothesis

Any disruption in the mitochondrial distribution along the optic nerve could be studied histochemically with the light microscope, using con-focal microscopy to visualise potentiometric fluorescent dyes that concentrate in mitochondria, and the electron microscope. Factors localising mitochondria in the optic nerve and mitochondrial–cytoskeletal interactions need to be better understood. Major difficulties in testing this hypothesis are the lack of availability of human optic nerves and the

Conclusions

We propose a common mitochondrial mechanism in optic neuropathies that selectively targets retinal ganglion cells as a consequence of the disruption of the normal physiological mitochondrial gradient at the optic nerve head. Our model moves away from the axoplasmic stasis theory at the lamina and suggests that the pathophysiology of optic neuropathies does not just involve a disorder of ATP production by mitochondria. The non-maintenance of the sharp mitochondrial gradient at the optic nerve

References (20)

There are more references available in the full text version of this article.

Cited by (0)

View full text