Interdependent Roles of PKM2 in Photoreceptors and RPE: Implications for Retinal Degeneration

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 accelerated retinal degeneration, underscoring the interdependence of photoreceptor and RPE metabolism. These findings identify PKM2 as a central regulator of retinal energy homeostasis and neuronal survival, offering new insight into mechanisms underlying photoreceptor and RPE degeneration in age-related macular degeneration.