Optic neuropathies – Importance of spatial distribution of mitochondria as well as function
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)
- et al.
Distribution of axonal and glial elements in the rhesus optic nerve head studied by electron microscopy
Am J Ophthalmol
(1976) Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy
Am J Ophthalmol
(1993)- et al.
Cytoplasmic architecture of the axon terminal: filamentous strands specifically associated with synaptic vesicles
Neuroscience
(1991) - et al.
The quantitative histochemistry of the retina
J Biol Chem
(1956) - et al.
Evidence of constriction of optic nerve axons at the lamina cribrosa in the normotensive eye in humans and other mammals
Ophthalmic Res
(1995) - et al.
The distribution of mitochondrial activity in relation to optic nerve structure
Arch Ophthalmol
(2002) - et al.
Histochemical localisation of mitochondrial enzyme activity in human optic nerve and retina
Brit J Ophthalmol
(1999) Leber hereditary optic neuropathy: how do mitochondrial DNA mutations cause degeneration of the optic nerve
J Bioenerg Biomembr
(1997)- et al.
The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation
Brain
(1995) - et al.
The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head
Brit J Ophthalmol
(2004)