Abstract
Photoreceptors, the primary site of phototransduction in the retina, require energy and metabolites to constantly renew their outer segments. They preferentially consume most glucose through aerobic glycolysis despite possessing abundant mitochondria and enzymes for oxidative phosphorylation (OXPHOS). Exactly how photoreceptors balance aerobic glycolysis and mitochondrial OXPHOS to regulate their survival is still unclear. We crossed rhodopsin-Cre mice with hexokinase 2 (HK2)-floxed mice to study the effect of knocking down HK2, the first rate-limiting enzyme in glycolysis, on retinal health and metabolic remodeling. Immunohistochemistry and Western blots were performed to study changes in photoreceptor-specific proteins and key enzymes in glycolysis and the tricarboxylic acid (TCA) cycle. Changes in retinal structure and function were studied by optical coherence tomography and electroretinography. Mass spectrometry was performed to profile changes in 13C-glucose-derived metabolites in glycolysis and the TCA cycle. We found that knocking down HK2 in rods led to age-related photoreceptor degeneration, evidenced by reduced expression of photoreceptor-specific proteins, age-related reductions of the outer nuclear layer, photoreceptor inner and outer segments and impaired electroretinographic responses. Loss of HK2 in rods led to upregulation of HK1, phosphorylation of pyruvate kinase muscle isozyme 2, mitochondrial stress proteins and enzymes in the TCA cycle. Mass spectrometry found that the deletion of HK2 in rods resulted in accumulation of 13C-glucose along with decreased pyruvate and increased metabolites in the TCA cycle. Our data suggest that HK2-mediated aerobic glycolysis is indispensable for the maintenance of photoreceptor structure and function and that long-term inhibition of glycolysis leads to photoreceptor degeneration.
Highlights
Photoreceptors, the primary site of phototransduction in the retina, require high energy and abundant metabolites to synthesize proteins and lipids for constant renewal of their outer segments[1,2,3]
The deletion of hexokinase 2 (HK2) was confirmed by IHC and Western blots using retinas from RHO-Cre mice crossed with HK2-floxed mice and age-matched WT controls
Western blots found that HK2 was reduced by ~95% in young and aged HKKO mice compared with agematched WT controls (Fig. 1D, E)
Summary
Photoreceptors, the primary site of phototransduction in the retina, require high energy and abundant metabolites to synthesize proteins and lipids for constant renewal of their outer segments[1,2,3]. They shed around 10% of their outer segments every day, resulting in full renewal of the outer segments every 10 days[1,4]. Photoreceptor degeneration, Photoreceptors preferentially metabolize glucose through aerobic glycolysis (the “Warburg Effect”) to meet their energetic and anabolic demand, they have abundant mitochondria for oxidative phosphorylation (OXPHOS)[15,16,17,18]. Hexokinase (HK), the first rate-limiting enzyme in glycolysis, has four isozymes.
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