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Imaging Ca2+ Dynamics in Cone Photoreceptor Axon Terminals of the Mouse Retina
Published on: May 6, 2015
A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon
Sean McCracken1, Minglei Zhao1, Kyler Squirrell1
1John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Retinal ganglion cells (RGCs) degenerate in optic neuropathies like glaucoma and traumatic optic nerve injury leading to irreversible vision loss. Higher levels of homeostatic Ca2+ and canonical Ca2+ regulated signaling promote RGC survival in animal models of glaucoma and optic nerve injury. Mitochondrial dysfunction is also a hallmark of degenerating neurons, including RGCs. Here, we investigate the intersection of mitochondrial function, Ca2+ homeostasis, and cellular resilience by performing an optic nerve crush model of RGC degeneration while monitoring and manipulating mitochondrial Ca2+ levels (mito-Ca2+). We find that mito-Ca2+ is predicative of RGC survival in that surviving RGCs are enriched for higher homeostatic mito-Ca2+ levels. Mitochondrial dysfunction was observed where mito-Ca2+ was reduced in RGCs after injury, regardless of survival. We then examined the importance of higher mito-Ca2+ in surviving RGCs by altering mito-Ca2+ levels and Ca2+ transit using pharmacological and AAV-mediated approaches. Paradoxically, treatment to decrease mito-Ca2+ increased survival to ONC. We then manipulated mito-Ca2+ permeability by altering the expression levels of the mitochondrial calcium uniporter (MCU) pore forming subunit that allows Ca2+ to enter mitochondria from the cytoplasm. Overexpressing MCU reduced RGC survival to injury, while shRNA knockdown of MCU increased RGC survival. These results reveal a complex relationship between mito-Ca2+ and RGC degeneration and suggest that well-surviving RGCs may be under chronic mitochondrial stress due to higher homeostatic mito-Ca2+ levels.
Insights
Higher mitochondrial calcium levels predict retinal ganglion cell (RGC) survival after injury. Paradoxically, reducing mitochondrial calcium or inhibiting the mitochondrial calcium uniporter (MCU) enhances RGC survival in optic nerve injury models.
Area of Science:
- Neuroscience
- Cell Biology
- Ophthalmology
Background:
- Retinal ganglion cells (RGCs) are crucial for vision and degenerate in optic neuropathies, causing irreversible vision loss.
- Mitochondrial dysfunction is a key feature of neuronal degeneration, including in RGCs.
- Calcium (Ca2+) homeostasis and signaling play a role in RGC survival following injury.
Purpose of the Study:
- To investigate the complex interplay between mitochondrial function, Ca2+ homeostasis, and RGC resilience after optic nerve injury.
- To determine the role of mitochondrial Ca2+ (mito-Ca2+) levels and transport in RGC survival and degeneration.
Main Methods:
- An optic nerve crush (ONC) model was used to induce RGC degeneration.
- Mitochondrial Ca2+ levels were monitored and manipulated using pharmacological agents and adeno-associated virus (AAV)-mediated gene delivery.
- The expression of the mitochondrial calcium uniporter (MCU) was altered to modulate Ca2+ influx into mitochondria.
Main Results:
- Higher homeostatic mito-Ca2+ levels were associated with RGC survival post-injury.
- Mitochondrial dysfunction, indicated by reduced mito-Ca2+, was observed in RGCs after injury, irrespective of survival.
- Pharmacological reduction of mito-Ca2+ and knockdown of MCU expression paradoxically increased RGC survival, while MCU overexpression reduced survival.
Conclusions:
- A complex, non-linear relationship exists between mito-Ca2+ dynamics and RGC degeneration.
- Elevated homeostatic mito-Ca2+ may indicate chronic mitochondrial stress in resilient RGCs.
- Modulating MCU activity presents a potential therapeutic strategy for enhancing RGC survival in optic neuropathies.
