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Published on: December 7, 2021
Interdependent roles of PKM2 in photoreceptors and RPE: implications for retinal degeneration
Ammaji Rajala1,2, Rahul Rajala3,4,5,6, Larissa J Trevino1,2
1Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Abstract:
Pyruvate kinase M2 (PKM2) functions as both a glycolytic enzyme and a transcriptional co-activator that coordinates metabolism and cell survival. Here, we define the developmental timing, cellular distribution, and physiological role of PKM isoforms in the mouse retina. PKM2 expression begins at postnatal day 2, preceding PKM1, and is highly enriched in photoreceptors, whereas PKM1 predominates in retinal ganglion cells. Conditional deletion of PKM2 in the retina, rods, or retinal pigment epithelium (RPE) demonstrated that PKM2 is essential for maintaining retinal structure and function. Loss of PKM2 impaired glycolytic activity, decreased ATP generation, and disrupted metabolic balance, leading to cellular disorganization and degeneration in both photoreceptors and the RPE. In the RPE, PKM2 deficiency decreased RPE65 protein levels and impaired the regeneration of 11-cis-retinal, disrupting the visual cycle. PKM2 deletion disrupted the normal cone opsin gradient, indicating that PKM2-dependent metabolic and transcriptional functions are essential for maintaining proper cone organization in the retina. Moreover, rod-specific deletion of PKM2 in Abca4 mutant mice showed early signs of retinal degeneration. The studies described in this manuscript highlight the interdependence of photoreceptor and RPE metabolism and show that PKM2 plays an important role in retinal energy homeostasis and neuronal survival, providing insight into the mechanisms underlying photoreceptor and RPE degeneration in age-related macular degeneration.
Insights
Pyruvate kinase M2 (PKM2) is crucial for mouse retinal structure and function. Its loss impairs energy production, leading to photoreceptor and retinal pigment epithelium degeneration, offering insights into macular degeneration.
Area of Science:
- Cell Biology
- Neuroscience
- Biochemistry
Background:
- Pyruvate kinase M2 (PKM2) is a key enzyme in glycolysis and a transcriptional co-activator.
- Understanding PKM isoforms' roles in the retina is vital for comprehending retinal health and disease.
Purpose of the Study:
- To investigate the developmental timing, cellular distribution, and physiological significance of PKM isoforms in the mouse retina.
- To elucidate the role of PKM2 in maintaining retinal structure, function, and metabolic homeostasis.
Main Methods:
- Conditional PKM2 deletion in mouse retinas, rods, and retinal pigment epithelium (RPE).
- Analysis of glycolytic activity, ATP generation, and metabolic balance.
- Assessment of RPE65 levels, visual cycle function, and cone opsin gradients.
- Evaluation of retinal degeneration in Abca4 mutant mice with rod-specific PKM2 deletion.
Main Results:
- PKM2 expression begins postnatally and is enriched in photoreceptors, while PKM1 is found in retinal ganglion cells.
- PKM2 deletion severely impacts retinal structure and function, causing photoreceptor and RPE degeneration.
- Loss of PKM2 disrupts glycolysis, reduces ATP, impairs the visual cycle, and affects cone organization.
- Rod-specific PKM2 deletion exacerbates degeneration in Abca4 mutant mice.
Conclusions:
- PKM2 is essential for retinal energy homeostasis, photoreceptor and RPE survival, and proper cone organization.
- PKM2 plays a critical role in coordinating metabolism and cell survival within the retina.
- These findings provide insights into mechanisms of retinal degeneration relevant to age-related macular degeneration.
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