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

View Article: PubMed Central - PubMed

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.

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Immunofluorescence analysis of PKM2 and PKM1 in mouse retinas.Prefer-fixed sections of dark- (A,B,F,G) and light-adapted (C,D,H,I) mouse retinas were stained for PKM2 (A–D), PKM1 (F–I), arrestin (B,D,G,I) and DAPI (B,D,E,G,I,J). Panels (B,D,G,I) represent the merged images of either PKM2 or PKM1 and arrestin, whereas panels (E,J) represent the omission of primary antibody. ROS, rod outer segments; RIS, rod inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar 50 μm.
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f1: Immunofluorescence analysis of PKM2 and PKM1 in mouse retinas.Prefer-fixed sections of dark- (A,B,F,G) and light-adapted (C,D,H,I) mouse retinas were stained for PKM2 (A–D), PKM1 (F–I), arrestin (B,D,G,I) and DAPI (B,D,E,G,I,J). Panels (B,D,G,I) represent the merged images of either PKM2 or PKM1 and arrestin, whereas panels (E,J) represent the omission of primary antibody. ROS, rod outer segments; RIS, rod inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar 50 μm.

Mentions: Retinal sections from dark- and light-adapted Balb/c (rod-dominant) and Nrl−/− (cone-dominant) mice were stained with PKM1 and PKM2 antibodies. Arrestin immunolocalization was used to confirm the adaptability of mice to dark- and light-adapted conditions. Under dark-adapted conditions, arrestin predominantly localized to rod inner segments and the outer plexiform layer (Fig. 1B,G). Upon light illumination, arrestin translocated to rod outer segments (Fig. 1D,I). Our results suggest that PKM2 expression was predominantly localized to rod inner segments and the outer plexiform layer in both dark- and light-adapted conditions (Fig. 1A,C). We did not observe any change in the localization of PKM2 under dark- or light-adapted conditions. We found that PKM1 was predominantly expressed in the rod inner plexiform layer and ganglion cell layer; some expression was also found in rod inner segments under both dark- and light-adapted conditions (Fig. 1F,H). The localization of PKM1 remained the same, irrespective of dark- or light-adapted conditions. These experiments suggest that both PKM2 and PKM1 are expressed in rod photoreceptor cells, and that PKM2 could be the predominant isoform in rods.


The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina
Immunofluorescence analysis of PKM2 and PKM1 in mouse retinas.Prefer-fixed sections of dark- (A,B,F,G) and light-adapted (C,D,H,I) mouse retinas were stained for PKM2 (A–D), PKM1 (F–I), arrestin (B,D,G,I) and DAPI (B,D,E,G,I,J). Panels (B,D,G,I) represent the merged images of either PKM2 or PKM1 and arrestin, whereas panels (E,J) represent the omission of primary antibody. ROS, rod outer segments; RIS, rod inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5121888&req=5

f1: Immunofluorescence analysis of PKM2 and PKM1 in mouse retinas.Prefer-fixed sections of dark- (A,B,F,G) and light-adapted (C,D,H,I) mouse retinas were stained for PKM2 (A–D), PKM1 (F–I), arrestin (B,D,G,I) and DAPI (B,D,E,G,I,J). Panels (B,D,G,I) represent the merged images of either PKM2 or PKM1 and arrestin, whereas panels (E,J) represent the omission of primary antibody. ROS, rod outer segments; RIS, rod inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar 50 μm.
Mentions: Retinal sections from dark- and light-adapted Balb/c (rod-dominant) and Nrl−/− (cone-dominant) mice were stained with PKM1 and PKM2 antibodies. Arrestin immunolocalization was used to confirm the adaptability of mice to dark- and light-adapted conditions. Under dark-adapted conditions, arrestin predominantly localized to rod inner segments and the outer plexiform layer (Fig. 1B,G). Upon light illumination, arrestin translocated to rod outer segments (Fig. 1D,I). Our results suggest that PKM2 expression was predominantly localized to rod inner segments and the outer plexiform layer in both dark- and light-adapted conditions (Fig. 1A,C). We did not observe any change in the localization of PKM2 under dark- or light-adapted conditions. We found that PKM1 was predominantly expressed in the rod inner plexiform layer and ganglion cell layer; some expression was also found in rod inner segments under both dark- and light-adapted conditions (Fig. 1F,H). The localization of PKM1 remained the same, irrespective of dark- or light-adapted conditions. These experiments suggest that both PKM2 and PKM1 are expressed in rod photoreceptor cells, and that PKM2 could be the predominant isoform in rods.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus