Metabolic Dysfunction in Glial Cells: Unraveling the Complexities of Glaucoma Pathology

Glaucoma, a leading cause of irreversible blindness globally, affects a staggering 80 million diagnosed patients, with an additional significant number undiagnosed. The hallmark of glaucoma is the progressive dysfunction and degeneration of retinal ganglion cells (RGCs) and their axons, constituting the optic nerve.

Established risk factors for glaucoma include age, genetics, and elevated intraocular pressure (IOP) (1). While current treatments primarily target IOP, a substantial number of patients experience continued vision loss despite IOP reduction or fail to achieve the desired IOP lowering (2). This underscores the urgent need for therapeutic interventions addressing the neurodegenerative aspects of glaucoma.

Metabolic Dysfunction as a Pivotal Player

Recent research has unveiled metabolic dysfunction as a key player in the pathology of glaucoma, interconnecting age-related factors, genetic predispositions, and elevated IOP (3). The evidence for metabolic insufficiency has emerged not only as an age-related decline in metabolic fitness but also as a potential genetic predisposition or a direct consequence of ocular hypertension. This revelation opens new avenues for understanding the intricate relationships between metabolism and neurodegeneration in glaucoma.

Metabolic Alterations Across Models

Metabolic dysfunction in glaucoma has been extensively studied in various animal models, predominantly rodent models that closely mimic human primary open-angle glaucoma (POAG) characteristics. These models have provided valuable insights into the metabolic changes occurring in different components of the visual system. Notably, these alterations are not confined to RGCs but extend to encompass the supporting cells within the visual system.

The Role of Glial Cells

Glial cells, crucial for maintaining homeostasis and supporting RGCs, play a pivotal yet understudied role in glaucoma-related metabolic alterations. While the importance of glial cells in shaping retinal metabolic pathways under normal conditions is well-established, their potential alterations in glaucoma remain less explored.

Limited Understanding of Glial Metabolism

The review acknowledges the scarcity of knowledge regarding how glial metabolism may be affected in glaucoma. Despite the known significance of glial cells in supporting RGCs, the specific metabolic changes within these cells in the context of glaucoma are not well understood. The review aims to bridge this gap by summarizing the current state of knowledge regarding metabolic alterations in glial cells in glaucoma.

Animal Models and Human Relevance

The findings presented in this review primarily originate from rodent models, providing insights into the metabolic changes associated with experimental glaucoma. While these models closely resemble human POAG, it is crucial to note that they may also exhibit features of other glaucoma subtypes. Human data supporting metabolic changes across the body predominantly comes from POAG patients, with some evidence from other subtypes. The interchangeable use of the term ‘glaucoma’ with POAG is reflective of this predominant focus.

Glial Metabolic Changes in Glaucoma

In the intricate landscape of glaucoma pathophysiology, the role of glial cells, including microglia, astrocytes, and Müller cells, is increasingly recognized as crucial. Inflammation, a well-established aspect of glaucoma, leads to shifts in glial phenotypes towards pro-inflammatory states, contributing to the damage of retinal ganglion cells (RGCs) and the optic nerve. While the mechanisms and consequences of inflammation in glaucoma have been extensively studied, this chapter delves into the less-explored territory of metabolic changes occurring in glial cells and their potential impact on neurodegeneration.

Pro-Inflammatory Shift in Glia:

The pro-inflammatory transformation of glial cells in glaucoma is driven by both neurodegenerative signaling from RGCs and direct stress induced by elevated intraocular pressure (IOP). Microglia populations undergo a phenotypic shift towards pro-inflammatory states, astrocytes and Müller cells experience reactive gliosis, and peripheral leukocytes infiltrate from the blood. This shift in glial phenotypes, while extensively studied in the context of inflammation, raises questions about the metabolic alterations that accompany or precede these changes and how they contribute to neurodegeneration in glaucoma.

Metabolic Stress in Glia:

Recent evidence suggests that glial cells themselves undergo metabolic stress in the early stages of glaucoma. AMP-activated protein kinase (AMPK), a key energy sensor and regulator, becomes activated in response to decreased intracellular ATP. This activation is not limited to RGCs but extends to glial cells, as evidenced by increased phosphorylated AMPK in astrocytes within the optic nerve of DBA/2J mice early in the disease. This activation may be in response to IOP-induced stress on glia rather than a sole reaction to RGC metabolic dysfunction.

Glial Metabolic Resilience:

Despite the metabolic stress, glial cells exhibit a degree of resilience in early glaucoma. In vitro studies demonstrated that chronic stretching of optic nerve head (ONH) astrocytes resulted in altered glycolytic and respiratory activity, indicating metabolic flexibility in response to elevated IOP. Glial cells, particularly astrocytes, play a crucial role in buffering metabolic depletion, as evidenced by studies showing increased glycogen depletion in the optic nerve during IOP elevation. However, this protective mechanism comes at a cost, as increased coupling through gap junctions propagates IOP-related metabolic stress through the visual system.

Microglial Metabolic Disruption:

RNA-sequencing of microglia in the optic nerve head of DBA/2J mice reveals early disruptions in metabolic regulation. Upregulation of mitochondrial transcripts, changes to oxidative phosphorylation, and dysregulation of glycolysis, gluconeogenesis, and lipid metabolism indicate early metabolic changes in microglia. The increase in hypoxia-inducible factor 1-alpha (Hif1a) expression, a master regulator of glycolysis, suggests a response to oxidative stress and inflammation.

Alternative Energy Substrates:

In response to low glucose availability and downregulation of monocarboxylate transporters, feeding DBA/2J mice a ketogenic diet proves protective. The ketogenic diet maintains monocarboxylate transporter levels, preserves retinal ganglion cells, and induces a robust antioxidant response. The mechanism behind the limit in glial inflammation remains unclear, whether directly attributable to increased alternative energy substrates available to glia or as a result of reduced intrinsic metabolic dysfunction and retinal ganglion cell degeneration.

Consequences of Glial Metabolic Changes:

Disruption to glial metabolism has far-reaching consequences. Mitochondrial dysfunction in Müller cells is associated with decreased ATP turnover and maximal respiration, potentially leading to decreased glutamate uptake and increased neurotoxicity. Oxidative stress in retinal glia further contributes to retinal ganglion cell death. The consequences of glial metabolic changes on their immune roles and inflammatory responses are yet to be fully explored, but evidence suggests a potential link between mitochondrial mutations and microglial activation.

Conclusion:

The exploration of glial metabolic changes in glaucoma opens a new frontier in understanding the intricate interplay between metabolism and neurodegeneration. While the field is in its infancy, the evidence presented here underscores the importance of unraveling the metabolic intricacies within glial cells. As research progresses, further insights into the consequences of glial metabolic alterations may pave the way for innovative therapeutic strategies targeting not only IOP but also the underlying metabolic dysregulation in glaucoma.

reference link : https://www.frontiersin.org/articles/10.3389/fopht.2023.1290465/full