Pyruvate kinase M2 isoform deletion in cone photoreceptors results in age-related cone degeneration

Abstract

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 this study, we conditionally deleted PKM2 in cones (cone-cre PKM2-KO) and found that loss of PKM2 results in the upregulation of PKM1 and a significant loss of cone function and cone degeneration in an age-dependent manner. Gene expression studies on cone-cre PKM2-KO show decreased expression of genes regulating glycolysis, PPP shunt, and fatty acid biosynthesis. Consistent with these observations, cones lacking PKM2 have significantly shorter cone outer segments than cones with PKM2. Our studies clearly suggest that PKM2 is essential for the anabolic process in cones to keep them alive for normal functioning and to support cone structure.

Selective knockdown of hexokinase 2 in rods leads to age-related photoreceptor degeneration and retinal metabolic remodeling

“…We next studied changes in 13 C-glucose-derived metabolites in the TCA cycle including M2 citrate, α-ketoglutarate, succinate, fumarate, and malate ( Fig. 7G-K).…”

“…Photoreceptor degeneration, including loss of photoreceptor outer segments (POS), is found in many retinal diseases including retinal detachment 5 , inherited retinal degenerations 6 , age-related macular degeneration 7 , diabetic macular edema 8 , and macular telangiectasia type 2 9 . Retinal metabolic dysfunction is a potential cause of photoreceptor degeneration 7,[10][11][12][13][14] .…”

Transduction of gluconeogenic enzymes prolongs cone photoreceptor survival and function in models of retinitis pigmentosa

“…The data on glucose-derived 13 C incorporation presented in Figure 1A and B are consistent with our previous finding that glycolysis plays a cell-autonomous role in photoreceptor anabolism 19 . Cones in the RP retina lose their OS prior to death, and recent evidence suggests that wild-type cones rely on aerobic glycolysis for maintenance of their OS and visual transduction (Rajala et al, 2018). This led us to hypothesize that, if glycolysis is inadequate, then augmentation of intracellular glycolytic intermediate(s) availability might improve the biosynthetic capacity of these cells and improve their function and/or survival.…”

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

“…21–24 PKM2 is expressed by photoreceptors in the retina while PKM1 expression is confined to the inner retina, and ML-265 shows a high degree of selectivity for PKM2 over other isoforms, PKM1, PKR, and PKL. 5,10,12,13,15,17,20–22 Therefore, ML-265 represents an ideal lead molecule to explore the neuroprotective effects of pharmacologically activating PKM2 in photoreceptors. In line with previous reports, ML-265 displayed potent activation of recombinant human PKM2 with a maximum activation of 249 ± 14% (best-fit value ± std.…”

“…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.…”