By Nicholas Garaffo, Biochemistry and Molecular Biology, 20’

Author Note: I wrote this paper in an attempt to connect my research project to a non-science audience. While this topic is very scientific, I am attempting to translate the molecular biology of the eye to a language any reader could understand. With this paper, I hope more people get interested in basic biology, and have a new appreciation for the eye.

Ode to the Eye

Right now, your irises are contracting, folding, and manipulating to adjust the amount of light allowed in. Photons are reflected from these words, move through your pupil, bypass the aqueous cavity within your eye, and are absorbed by the .2 mm thick retinal cell layer inside your eye (1, 2). These photons are scattered, and absorbed by the photoreceptor cells; these are known as rods and cones. Once absorbed, the cells undergo a rapid change in their membrane potential allowing the signal to transport along its axon. The signal is released from the photoreceptors and received by the bipolar cells which then undergo the same process. Hundreds of photoreceptor cells connect to a single bipolar cell, and hundreds of bipolar cells connect to a single retinal ganglion cell (RGC) (1, 2). RGCs are the bridge between the eye and brain. Without these cells the light ends as a signal, and is never used to create an image. All of this is happening as fast as you can read these words; what a beautiful thing the eye is!

Introduction

The cells within the eye are co-dependent for its overall performance, yet even the smallest alterations can be detrimental. As a fluid filled cavity, the eye expands and contracts in response to external pressures. This is a normal process because every time you blink, rub your eye, or sneeze the pressure within the eye– intraocular pressure (IOP)– spikes. An IOP above 22 mmHg (16-22 mmHg is thought to be physiologically normal) can occur when the muscles, known as the ciliary bodies, responsible for flushing and recycling the internal fluid get clogged (3). Fluid will then begin to increase within the eye, and cause the cavity to expand. While spikes in IOP are rarely damaging, prolonged exposure to high IOP can strain RGCs. Recall, RGCs are the bridge between the eye and the brain. RGCs exit the eye through a pore in the back of the eye, known as the optic nerve head (ONH).  To protect and accelerate the signal from the eye to the brain, RGC’s form a tubular structure with other cell types. This structure is called the optic nerve and is composed of RGC’s, blood vasculature, and microglia– a large family of neuronal support cells, but for the focus of this review we will only focus on specifically the astrocytes.

The main area for RGC damage is the ONH, the connecting area of the eye to the optic nerve (2, 3). Like all neuron cells, the axons of RGCs are heavily myelinated– a fatty sheath to increase electrical signaling– however, the RGCs which exit through the eye must remain unmyelinated to maintain the eye’s dynamic motions. These ONH RGCs are most vulnerable to variations in IOP. When the eye’s IOP increases for a prolonged period of time, the ONH and its corresponding cells are pulled. This increase in tension causes cellular strain, and as a consequence, glaucoma– an irreversible blindness commonly attributed to a prolonged increase in IOP (3). Patients first notice blind spots in the periphery, and then the blind spot begins to rainbow across their vision until it elapses the entire eye. Currently, there is no cure, and the main treatments are to decrease IOP, but regulating IOP serves to prolong vision rather than prevent glaucoma.

Interestingly, only 25-50% of all patients with glaucoma have high IOP, and patients with high IOP do not always get glaucoma (2, 3). Increases in IOP may be a correlation with glaucoma rather than a cause of it. Therefore, it is of extreme importance to understand overall RGC health through other methods. Specific research is focused on how debris, including fats, organelles and degraded protein, is moved throughout the optic nerve. 

Astrocytes and Retinal Ganglion Cells

Astrocytes are a cell-type within the glial system that interact with neurons to provide metabolic support, signaling and maintain cellular homeostasis. Throughout the entire neuronal network, (brain, spine, optic nerve, etc.) neurons do not exist in isolation. Within the brain, astrocytes are responsible for sending local and wide-ranging signals which actually assist in neuronal communication (4). Within the optic nerve, astrocytes surround every part of RGC that is not covered in myelin to assist similar activities. Astrocytes actually out-number RGCs within the optic nerve.

Recall that neurons function by sending neurotransmitters, most commonly glutamic acid, across synapses to relay information cell to cell. This process is no different for RGCs. Each signal must remain short, and sharp to ensure proper communication. One function that astrocytes play is to uptake lingering glutamic acid when a signal is released thereby preventing misfiring. The sequestered glutamic acid will be converted to glutamine within the astrocyte and sent back to the RGC for future signaling (4). This is only one of the hundreds of functions that astrocytes help RGC’s with.

Transmitophagy and Implications with Glaucoma

Mitochondria, colloquially known as the power-house of the cell, are an indicator of overall cell health because abnormal or reduced amounts of mitochondria are symptomatic of degratory diseases, including parkinson’s disease and glaucoma. Mitochondria normally function to provide the cell with ample ATP through the electron-transport chain which requires a reactive oxygen species (ROS) and electron potential forces (5). As mitochondria age, their ROS begin to interact with their intracellular proteins, including that of the electron transport chain. When the damage accumulates, the mitochondria undergoes fission (i.e. pinching off a piece) to be degraded via the lysosome, or fusion (i.e. fuse to a large, healthy mitochondria) (5). For the context of this article we will only be looking at lysosomal mediated degradation of mitochondria, and mitochondria fragments. This process is known as mitophagy, which is a subset of autophagy. One assumption made with autophagy (or, ‘self-eating’) is that cells will degrade their own organelles. While this may be the case for the majority of degradative processes, there is evidence which supports RGC protrusion of mitochondria to be degraded by neighboring astrocytes, a novel process termed transmitophagy.

In 2014, Chung-Ha et al. provided a new model of mitochondria degradation within ONH RGC’s (6). This study used the Xenopus laevis as their model, and used a series of mitochondria, lysosomal, and astrocytic tags to track mitochondria movement and degradation within the optic nerve. Ultimately, they found fragmented and malformed mitochondria protruding out from the RGC axon, and getting picked up by neighboring astrocytes for degradation (6). Axonal mitochondria are specifically vulnerable to this process because it is an energy costly, and dangerous process to move an ROS-producing mitochondria to the cell soma, where the majority of lysosomes reside.

Conclusion

The eye is a beautiful, yet intricate structure that is dependent on overall cell and organelle health. The mitochondria are perhaps the most important for cellular metabolism and overall health. While it was previously thought that mitochondria are only degraded within the cell, transmitophagy illustrates a potential route that axonal mitochondria can undergo for degradation. However, transmitophagy studies have only been presented in non-disease models. Therefore, future studies must utilize disease models (i.e. induced glaucoma models) to understand how transmitophagy is affected, or affects, eye diseases.

Citations

1. Kolb H. Gross Anatomy of the Eye. 2005 May 1. “The Organization of the Retina and Visual System. Salt Lake City (UT): University of Utah Health Sciences Center; 1995.
2. Sung, Ching-Hwa, and Jen-Zen Chuang. “The cell biology of vision.” The Journal of cell biology vol. 190,6 (2010): 953-63. doi:10.1083/jcb.201006020
3. Weinreb, Robert N et al. “The pathophysiology and treatment of glaucoma: a review.” JAMA vol. 311,18 (2014): 1901-11. doi:10.1001/jama.2014.3192
4. Sofroniew, Michael V, and Harry V Vinters. “Astrocytes: biology and pathology.” Acta neuropathologica vol. 119,1 (2010): 7-35. doi:10.1007/s00401-009-0619-8
5. Pickrell, Alicia M, and Richard J Youle. “The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease.” Neuron vol. 85,2 (2015): 257-73. doi:10.1016/j.neuron.2014.12.007
6. Davis, Chung-ha O et al. “Transcellular degradation of axonal mitochondria.” Proceedings of the National Academy of Sciences of the United States of America vol. 111,26 (2014): 9633-8. doi:10.1073/pnas.1404651111