The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

Abstract

The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs.

A mutation in transmembrane protein 135 impairs lipid metabolism in mouse eyecups

“…Our current study builds on previous work that identified TMEM135 as a key protein involved in mitochondrial dynamics 3 , 7 , 20 , 21 , metabolic regulation 8 and oxidative stress in mice 3 . However, the molecular function of TMEM135 remains elusive.…”

Treatment of Glaucoma with Natural Products and Their Mechanism of Action: An Update

“…As reviewed by others, perhaps the most accepted hypothesis involved in glaucoma pathogenesis currently may include the mechanical damage to the ONH induced by increased IOP, followed by vascular dysregulation (reduced ocular blood flow) and neuroinflammation (glial activation), which then disrupt axonal transport due to axonal mitochondrial function loss in the RGCs, ultimately leading to RGC axonal degeneration and RGC cell death (Figure 1) [58][59][60]. However, the combination of mechanisms described earlier may vary greatly among different glaucoma patients [60].…”

The Role of Axonal Transport in Glaucoma

“…Neurons have a particularly polarized cell morphology that makes transport even more important, with several projections, including dendrites and a long axon, which extend far from the cell body, where most cell machinery is located [ 14 , 63 ]. In particular, the axons of RGCs span a considerable length running from the retina to the superior colliculus and the lateral geniculate nucleus at the posterior part of the brain [ 64 , 65 ]. Axonal transport is an ATP-dependent process, during which cytoskeleton-associated motor proteins actively carry different types of cargos along microtubules in the axons [ 15 ].…”

“…RGCs present some particular features which could make them even more prone to axonal transport disruptions. They are projection neurons with lengthy axons, estimated to reach 50–100 mm in primates, relying therefore on long-distance axonal transport [ 65 ]. Furthermore, the inner retina, where those cells are located, is known to have a high energy demand, and the ONH has normally an increased mitochondria density, a sign of more energy requirement.…”

“…In this sense, RGC axonal transport might be very sensitive to reductions in energy availability. Moreover, RGC axons present an unusual anatomy, as they bend up to 90° to leave the eye to form the optic nerve, which could add up as a physical challenge to axonal transport [ 65 ]. When leaving the eye, axons pass through the porous structure of the lamina and face a pressure gradient in the ONH region, between the intraocular and CSF pressures, which in the human eye with a normal IOP is estimated to be 3.5 mm Hg, potentially a further stressor [ 93 ].…”