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Raju V S Rajala, Yuhong Wang, Krutik Soni, Ammaji Rajala; Pyruvate Kinase M2 Isoform Deletion in Cone Photoreceptors Results in Age-Related Cone Degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2378.
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© ARVO (1962-2015); The Authors (2016-present)
The tumor form of pyruvate kinase M2 has been suggested to promote cellular anabolism by redirecting the metabolism to cause accumulation of glycolytic intermediates and increasing flux through the pentose phosphate pathway, which is a metabolic pathway parallel to glycolysis. Both rod and cone photoreceptors express the tumor form of pyruvate kinase M2. Recent studies from our laboratory show that PKM2 is functionally important for rod photoreceptor structure, function, and viability. However, the functional role of PKM2 in cones is not known. In the present study, we conditionally deleted PKM2 and studied its effect on cone photoreceptor structure and function.
We bred mice expressing Cre-recombinase in cones to mice with a floxed PKM2 gene, generating offspring with a conditional deletion of PKM2 in cone photoreceptors (cone-cre PKM2-KO). Cre recombinase, PKM2, and PKM1 expression were examined by immunohistochemical analysis. Cone density and cone outer segment length were examined by peanut agglutinin (PNA) staining. Cone function was measured by electroretinography. Real-time PCR was employed to examine the gene expression of glycolysis, pentose phosphate pathway (PPP), and fatty acid biosynthesis.
Cre-expression was properly targeted to cone-photoreceptor nuclei. Disruption of PKM2 in cones resulted in a compensatory increase in PKM1. Our results show that deletion of PKM2 in cones resulted in a significant loss of cone function and cone degeneration in an age-dependent manner. Gene expression studies on cone-cre PKM2-KO demonstrated decreased expression of genes regulating glycolysis, PPP, and fatty acid biosynthesis. Consistent with these observations, cones lacking PKM2 have significantly shorter cone outer segments than do cones with PKM2.
Our findings clearly demonstrate that loss of PKM2 expression upregulates PKM1 expression. Our studies suggest that PKM2 is essential for the anabolic process in cones to keep them alive for normal functioning and to support cone structure.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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