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.

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

“…Mohammad et al [ 232 ] found that the use of TEPP-46 significantly enhanced PK activity in pancreatic cancer cells, downregulated PKM2 dimer expression, and inhibited the growth of tumors in a mouse model. In addition, many molecules, such as parthenolide (PTL 5) ( Figure 6 I) [ 233 ], ML-265 ( Figure 6 K) [ 234 ], PA-12 [ 235 ], Pyridin-3 ylmethyl carbamodithioic esters [ 236 ], ZINC08383544 [ 237 ], and compound 0089-0022 [ 238 ], inhibit tumor growth as PKM2 agonists. Some researchers have also explored the effects of herbal components on PKM2 enzyme activity.…”

Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration

“…Here we show that RTBDN ablation can affect the rate of glycolysis in a similar manner as Pkm2 −/− , but promoting PPP to meet the enhanced need of free-radical scavenging only serves as a short-term coping mechanism, and soon degeneration ensues. This strategy seems partially similar to therapeutic approaches suggested for acute stress conditions (20,38). An important feature of our research is that it determined the factors that precede, and may lead to, functional decline and eventual degeneration, providing critical insights into the primary causes behind retinal degeneration.…”

Dihydropyrimidinase Like 2 Promotes Bladder Cancer Progression via Pyruvate Kinase M2-Induced Aerobic Glycolysis and Epithelial–Mesenchymal Transition

“…It is well-established that the less active PKM2 dimer drives aerobic glycolysis, whereas the active PKM2 tetramer produces pyruvate for oxidative phosphorylation ( Christofk et al, 2008 ; Hitosugi et al, 2009 ; Anastasiou et al, 2012 ). The mechanisms involved in the PKM2 dimer-tetramer dynamics include fructose-1,6-biphosphate-mediated PKM2 tetramerization ( Dombrauckas et al, 2005 ), tyrosine phosphorylation ( Yang, 2015 ), acetylation ( Prakasam et al, 2018 ), and modulation by small molecule PKM2 activators ( Wubben et al, 2020 ). In the present study, we identified DPYSL2 as a novel regulator that promotes the conversion of PKM2 tetramers to dimers.…”