The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina

Abstract

The tumor form of pyruvate kinase M2 (PKM2) undergoes tyrosine phosphorylation and gives rise to the Warburg effect. The Warburg effect defines a pro-oncogenic metabolism switch such that cancer cells take up more glucose than normal tissue and favor incomplete oxidation of glucose, even in the presence of oxygen. Retinal photoreceptors are highly metabolic and their energy consumption is equivalent to that of a multiplying tumor cell. In the present study, we found that PKM2 is the predominant isoform in both rod- and cone-dominant retina, and that it undergoes a light-dependent tyrosine phosphorylation. We also discovered that PKM2 phosphorylation is signaled through photobleaching of rhodopsin. Our findings suggest that phosphoinositide 3-kinase activation promotes PKM2 phosphorylation. Light and tyrosine phosphorylation appear to regulate PKM2 to provide a metabolic advantage to photoreceptor cells, thereby promoting cell survival.

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…Photoreceptors express high levels of enzyme isoforms that favor the conversion of pyruvate into lactate, including hexokinase II (HKII), the pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase subunit A, LDHA (Aït-Ali et al, 2015; Chinchore et al, 2017; Casson et al, 2016 Lindsay et al, 2014; Rajala et al, 2016; Reidel et al, 2011). Hexokinase catalyzes the first reaction of glycolysis via the phosphorylation of glucose.…”

“…This enzyme is also preferentially expressed in rapidly dividing cells including cancer cells. While some controversy exists regarding the expression of PKM1 in photoreceptors, with some reporting the absence of PKM1 and others observing it (Chinchore et al, 2017; Casson et al, 2016; Lindsay et al, 2014; Rajala et al, 2016; Rueda et al, 2016), PKM2 is indisputably the dominant isoform in photoreceptors.…”

“…Rajala et al observed PI3K-mediate phosphorylation of PKM2 with light stimulation, leading to enzyme inhibition, suggesting a reduced production of pyruvate with light and potentially a build-up of glycolytic intermediates leading to anabolic reactions (Rajala et al, 2016). Chinchore et al have recently shown that impairing glycolysis specifically in rods with a variety of methods (interfering with the activity of LDHA, PFK, and PK) leads to shorter rod outer segments (OS), which is thought to be the result of reduced OS synthesis (Chinchore et al, 2017).…”

“…The lack of expression of various glycolytic enzymes in Müller glia further suggests that these cells do not have high glycolytic rates in vivo . Several groups have noted the lack of pyruvate kinase (PKM1 or PKM2) in Müller glia in the rodent retina (Casson et al, 2016; Lindsay et al, 2014; Rajala et al, 2016). It has also been noted that Müller glia do not express LDHA (Casson et al, 2016) but may express LDHB (Chinchore et al, 2017).…”

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection

“…Photoreceptors maintain expression of PKM2 after differentiation, unlike other neurons, which exclusively express the constitutively active PKM1 isoform following terminal differentation. 5,13,15–17 PKM2 activity is tightly regulated whereas PKM1 is constitutively active. 8 As a tetramer, PKM2 displays high catalytic activity and is associated with increased ATP synthesis and catabolic metabolism.…”