inzicht - Neuroscience - # Axonal mitophagy and mitochondrial shedding in glaucoma

Glaucoma-associated Optineurin Mutations Increase Axonal Mitophagy and Shedding of Mitochondria in a Vertebrate Optic Nerve Model

Q: How might the increased shedding and astrocytic degradation of mitochondria from RGC axons contribute to the axonal degeneration observed in glaucoma?

The increased shedding of mitochondria from retinal ganglion cell (RGC) axons, particularly in the context of glaucoma-associated mutations in the Optineurin (OPTN) gene, can significantly contribute to axonal degeneration through several mechanisms. First, the process of transmitophagy, where damaged or dysfunctional mitochondria are shed and subsequently degraded by surrounding astrocytes, is essential for maintaining mitochondrial quality control. In glaucoma, mutations in OPTN lead to an increase in the shedding of mitochondria, which may overwhelm the astrocytic capacity to effectively degrade these organelles. This accumulation of excess mitochondria outside of RGC axons can result in a toxic environment, leading to oxidative stress and inflammation, both of which are known contributors to neurodegeneration. Moreover, the increased presence of mitochondria outside of axons may disrupt the normal metabolic support that astrocytes provide to RGCs. Astrocytes play a crucial role in maintaining neuronal health by regulating energy metabolism and providing neuroprotective factors. When astrocytes are burdened with excessive mitochondrial debris, their ability to support RGCs diminishes, potentially leading to energy deficits and further exacerbating axonal degeneration. Additionally, the dysregulation of mitophagy due to OPTN mutations may impair the selective removal of damaged mitochondria, resulting in the accumulation of dysfunctional mitochondria within RGC axons, which can lead to axonal transport deficits and ultimately contribute to the degeneration of RGC axons observed in glaucoma.

Q: What other cellular pathways or mechanisms might be disrupted by glaucoma-associated OPTN mutations that could also contribute to RGC axon degeneration?

Glaucoma-associated mutations in OPTN may disrupt several cellular pathways beyond mitophagy that contribute to RGC axon degeneration. One significant pathway is the autophagy-lysosomal pathway, which is crucial for the degradation of cellular debris and damaged organelles. Mutations in OPTN can impair the recruitment of autophagic machinery, leading to the accumulation of autophagic vesicles and cellular waste within RGCs. This accumulation can induce cellular stress and apoptosis, further contributing to axonal degeneration. Additionally, the dysregulation of protein homeostasis due to impaired ubiquitin-proteasome system (UPS) function may also play a role. OPTN is involved in the recognition and targeting of ubiquitinated proteins for degradation. Mutations in OPTN can lead to the accumulation of misfolded or aggregated proteins, which can disrupt cellular function and contribute to neurodegenerative processes. Furthermore, the disruption of signaling pathways related to inflammation and oxidative stress response may occur, as OPTN is implicated in modulating inflammatory responses. The chronic inflammation associated with RGC degeneration in glaucoma can exacerbate neuronal damage and promote axonal degeneration. Lastly, alterations in mitochondrial dynamics, including fission and fusion processes, may also be affected by OPTN mutations. Proper mitochondrial dynamics are essential for maintaining mitochondrial function and distribution within neurons. Disruption of these processes can lead to mitochondrial fragmentation, impaired energy production, and increased susceptibility to apoptosis, all of which can contribute to RGC axon degeneration in glaucoma.

Q: Given the role of mitochondrial dysfunction in neurodegenerative diseases, could the insights from this study on axonal mitophagy and mitochondrial shedding have broader implications for understanding pathogenic mechanisms in other neurological disorders?

The insights gained from this study on axonal mitophagy and mitochondrial shedding in the context of glaucoma have significant implications for understanding pathogenic mechanisms in other neurodegenerative diseases. Mitochondrial dysfunction is a common feature across various neurological disorders, including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). The mechanisms of transmitophagy and the role of OPTN in mitochondrial quality control may be relevant in these conditions as well. For instance, the dysregulation of mitophagy observed in glaucoma could similarly contribute to the accumulation of damaged mitochondria in other neurodegenerative diseases, leading to increased oxidative stress and neuronal cell death. The study highlights the importance of local mitochondrial degradation mechanisms, such as transmitophagy, which may be compromised in other diseases, resulting in the failure to clear dysfunctional mitochondria from distal axonal regions. Moreover, the findings regarding the shedding of mitochondria and their subsequent degradation by neighboring glial cells may provide insights into the interactions between neurons and glial cells in other neurodegenerative contexts. The ability of astrocytes to manage mitochondrial debris could be crucial in maintaining neuronal health, and any impairment in this process could exacerbate neurodegeneration. Overall, the study underscores the need for further research into the role of mitochondrial dynamics and quality control mechanisms in various neurological disorders, potentially leading to novel therapeutic strategies aimed at enhancing mitophagy and mitochondrial health to mitigate neurodegenerative processes.

Belangrijkste concepten

Glaucoma-associated mutations in the mitophagy receptor Optineurin (OPTN) increase the fraction of stationary mitochondria, OPTN, and LC3b within retinal ganglion cell (RGC) axons, as well as the shedding of mitochondria from axons and their subsequent degradation by surrounding astrocytes.

Samenvatting

The study investigates the effects of glaucoma-associated mutations in the mitophagy receptor Optineurin (OPTN) on the behavior of mitochondria and mitophagy machinery within retinal ganglion cell (RGC) axons in a Xenopus laevis tadpole model.

Key findings:

Under basal conditions, approximately half of axonal mitochondria in RGCs are stationary, with the remaining mitochondria moving anterogradely and retrogradely.
Expression of glaucoma-associated OPTN mutants, but not wild-type OPTN or ALS-associated OPTN mutants, increases the fraction of stationary mitochondria, OPTN, and LC3b within RGC axons.
The increased stationary mitochondria and OPTN colocalize, suggesting an increase in axonal mitophagy.
Glaucoma-associated OPTN mutants also increase the amount of mitochondria and OPTN found outside of the RGC axons, both within the optic nerve parenchyma and on the surface of the optic nerve.
Correlative light-EM analysis shows that the extra-axonal mitochondria are degraded by surrounding astrocytes, a process referred to as "transmitophagy".
Live-imaging reveals that the mitochondria and OPTN leave the RGC axons in the form of axonal "exophers" - protrusions that are pinched off from the axons.

These findings support a model where glaucoma-associated OPTN mutations lead to increased axonal mitophagy and shedding of mitochondria, which are then degraded by surrounding astrocytes, potentially contributing to axonal degeneration in glaucoma.

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biorxiv.org

Statistieken

Approximately 50% of axonal mitochondria in retinal ganglion cells are stationary.
The average speed of anterogradely and retrogradely moving mitochondria is 0.63 μm/s and 0.78 μm/s, respectively.
Expression of the glaucoma-associated OPTN mutant E50K increases the fraction of mitochondria and OPTN outside of the RGC axons to 35.8% and 21.8%, respectively, compared to 15.2% and 5.7% for wild-type OPTN.

Citaten

"Expression of E50K OPTN, in addition to resulting in the stalling of large number of mitochondria, OPTN and LC3b within axons and colocalization of mitochondria and OPTN, also significantly increases the amount of both OPTN and mitochondria that are found outside of the axons."
"Notably, while axonal debris was most often observed within astrocyte fine processes, often those processes were closely associated with fine processes of distinct astrocytes."

Belangrijkste Inzichten Gedestilleerd Uit

Glaucoma-associated Optineurin mutations increase transmitophagy in a vertebrate optic nerve

by Jeong,Y., Da... om www.biorxiv.org 05-30-2023

https://www.biorxiv.org/content/10.1101/2023.05.26.542507v1

Diepere vragen

How might the increased shedding and astrocytic degradation of mitochondria from RGC axons contribute to the axonal degeneration observed in glaucoma?

The increased shedding of mitochondria from retinal ganglion cell (RGC) axons, particularly in the context of glaucoma-associated mutations in the Optineurin (OPTN) gene, can significantly contribute to axonal degeneration through several mechanisms. First, the process of transmitophagy, where damaged or dysfunctional mitochondria are shed and subsequently degraded by surrounding astrocytes, is essential for maintaining mitochondrial quality control. In glaucoma, mutations in OPTN lead to an increase in the shedding of mitochondria, which may overwhelm the astrocytic capacity to effectively degrade these organelles. This accumulation of excess mitochondria outside of RGC axons can result in a toxic environment, leading to oxidative stress and inflammation, both of which are known contributors to neurodegeneration.
Moreover, the increased presence of mitochondria outside of axons may disrupt the normal metabolic support that astrocytes provide to RGCs. Astrocytes play a crucial role in maintaining neuronal health by regulating energy metabolism and providing neuroprotective factors. When astrocytes are burdened with excessive mitochondrial debris, their ability to support RGCs diminishes, potentially leading to energy deficits and further exacerbating axonal degeneration. Additionally, the dysregulation of mitophagy due to OPTN mutations may impair the selective removal of damaged mitochondria, resulting in the accumulation of dysfunctional mitochondria within RGC axons, which can lead to axonal transport deficits and ultimately contribute to the degeneration of RGC axons observed in glaucoma.

What other cellular pathways or mechanisms might be disrupted by glaucoma-associated OPTN mutations that could also contribute to RGC axon degeneration?

Glaucoma-associated mutations in OPTN may disrupt several cellular pathways beyond mitophagy that contribute to RGC axon degeneration. One significant pathway is the autophagy-lysosomal pathway, which is crucial for the degradation of cellular debris and damaged organelles. Mutations in OPTN can impair the recruitment of autophagic machinery, leading to the accumulation of autophagic vesicles and cellular waste within RGCs. This accumulation can induce cellular stress and apoptosis, further contributing to axonal degeneration.
Additionally, the dysregulation of protein homeostasis due to impaired ubiquitin-proteasome system (UPS) function may also play a role. OPTN is involved in the recognition and targeting of ubiquitinated proteins for degradation. Mutations in OPTN can lead to the accumulation of misfolded or aggregated proteins, which can disrupt cellular function and contribute to neurodegenerative processes. Furthermore, the disruption of signaling pathways related to inflammation and oxidative stress response may occur, as OPTN is implicated in modulating inflammatory responses. The chronic inflammation associated with RGC degeneration in glaucoma can exacerbate neuronal damage and promote axonal degeneration.
Lastly, alterations in mitochondrial dynamics, including fission and fusion processes, may also be affected by OPTN mutations. Proper mitochondrial dynamics are essential for maintaining mitochondrial function and distribution within neurons. Disruption of these processes can lead to mitochondrial fragmentation, impaired energy production, and increased susceptibility to apoptosis, all of which can contribute to RGC axon degeneration in glaucoma.

Given the role of mitochondrial dysfunction in neurodegenerative diseases, could the insights from this study on axonal mitophagy and mitochondrial shedding have broader implications for understanding pathogenic mechanisms in other neurological disorders?

The insights gained from this study on axonal mitophagy and mitochondrial shedding in the context of glaucoma have significant implications for understanding pathogenic mechanisms in other neurodegenerative diseases. Mitochondrial dysfunction is a common feature across various neurological disorders, including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). The mechanisms of transmitophagy and the role of OPTN in mitochondrial quality control may be relevant in these conditions as well.
For instance, the dysregulation of mitophagy observed in glaucoma could similarly contribute to the accumulation of damaged mitochondria in other neurodegenerative diseases, leading to increased oxidative stress and neuronal cell death. The study highlights the importance of local mitochondrial degradation mechanisms, such as transmitophagy, which may be compromised in other diseases, resulting in the failure to clear dysfunctional mitochondria from distal axonal regions.
Moreover, the findings regarding the shedding of mitochondria and their subsequent degradation by neighboring glial cells may provide insights into the interactions between neurons and glial cells in other neurodegenerative contexts. The ability of astrocytes to manage mitochondrial debris could be crucial in maintaining neuronal health, and any impairment in this process could exacerbate neurodegeneration.
Overall, the study underscores the need for further research into the role of mitochondrial dynamics and quality control mechanisms in various neurological disorders, potentially leading to novel therapeutic strategies aimed at enhancing mitophagy and mitochondrial health to mitigate neurodegenerative processes.