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.
Highlights
In order to better understand the role of mitochondria in neurodegeneration, it is important to appreciate the wide variety of functions these organelles have in cells
Passive contributions include features of these organelles that lead to impairment of respiratory activity, such that cells are unable to meet challenges they face during times of stress. This effect is primarily attributed to defects in mitochondrial dynamics and encompasses genetic mutations in genes involved in fission and fusion, as well as mitophagy
These cells break down stores of glycogen and pass lactate through the so-called Astrocyte to Neuron L-lactate shuttle (ANLS) using the monocarboxylate transporter MCT1 [102,103,104]
Summary
Fusion occurs in response to changes in demand for oxidative phosphorylation and is thought to increase resiliency of mitochondria by the combining of organelles with weaker function (i.e., reduced membrane potential caused by aging) with more robust ones [6] This process has been reported in cells undergoing mild stress and may help to reduce the need for an increase in mitochondrial clearance. In this case, aged or damaged mitochondria, associated with high levels of PINK1, Parkin, and ubiquitin, are packaged into vesicular evulsions that are taken up by adjacent cells for degradation [35] This process may play an important role in the normal physiology, and disease, of mitochondria in neurons with long projection axons and will be discussed in detail below.
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