Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis.

Abstract

Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. Similar to cancer cells, photoreceptors maintain pyruvate kinase muscle isoform 2 (PKM2) expression, which is a critical regulator in aerobic glycolysis. Unlike PKM1, which has constitutively high catalytic activity, PKM2 is under complex regulation. Recently, we demonstrated that genetically reprogramming photoreceptor metabolism via PKM2-to-PKM1 substitution is a promising neuroprotective strategy. Here, we explored the neuroprotective effects of pharmacologically activating PKM2 via ML-265, a small molecule activator of PKM2, during acute outer retinal stress. We found that ML-265 increased PKM2 activity in 661 W cells and in vivo in rat eyes without affecting the expression of genes involved in glucose metabolism. ML-265 treatment did, however, alter metabolic intermediates of glucose metabolism and those necessary for biosynthesis in cultured cells. Long-term exposure to ML-265 did not result in decreased photoreceptor function or survival under baseline conditions. Notably, though, ML-265-treatment did reduce entrance into the apoptotic cascade in in vitro and in vivo models of outer retinal stress. These data suggest that reprogramming metabolism via activation of PKM2 is a novel, and promising, therapeutic strategy for photoreceptor neuroprotection.

• Authors: Thomas J Wubben, Mercy Pawar, Eric Weh, Andrew Smith, Peter Sajjakulnukit, Li Zhang, Lipeng Dai, Heather Hager, Manjunath P Pai, Costas A Lyssiotis, Cagri G Besirli
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 2990 (02 19 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32076076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Activators
• ML-265
• Protein Isoforms
• Pyridazines
• Pyrroles
• Pyruvate Kinase

Topics

• Animals
• Apoptosis (drug effects)
• Blindness (etiology, prevention & control)
• Cell Line
• Disease Models, Animal
• Enzyme Activators (pharmacology, therapeutic use)
• Glycolysis (drug effects)
• Humans
• Intravitreal Injections
• Male
• Mice
• Mice, Knockout
• Photoreceptor Cells (drug effects, pathology)
• Protein Isoforms (agonists, metabolism)
• Pyridazines (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)
• Pyruvate Kinase (genetics, metabolism)
• Rabbits
• Rats
• Retinal Diseases (complications, drug therapy, pathology)