ABSTRACT
The postmitotic retina is highly metabolic and the photoreceptors depend on aerobic glycolysis for an energy source and cellular anabolic activities. Lactate dehydrogenase A (LDHA) is a key enzyme in aerobic glycolysis, which converts pyruvate to lactate. Here we show that cell-type-specific actively translating mRNA purification by translating ribosome affinity purification shows a predominant expression of LDHA in rods and cones and LDHB in the retinal pigment epithelium and Müller cells. We show that genetic ablation of LDHA in the retina resulted in diminished visual function, loss of structure, and a loss of dorsal-ventral patterning of the cone-opsin gradient. Loss of LDHA in the retina resulted in increased glucose availability, promoted oxidative phosphorylation, and upregulated the expression of glutamine synthetase (GS), a neuron survival factor. However, lacking LDHA in Müller cells does not affect visual function in mice. Glucose shortage is associated with retinal diseases, such as age-related macular degeneration (AMD), and regulating the levels of LDHA may have therapeutic relevance. These data demonstrate the unique and unexplored roles of LDHA in the maintenance of a healthy retina.
ABSTRACT
Insulin-like growth factor I (IGF-1) is a neurotrophic factor and is the ligand for insulin-like growth factor 1 receptor (IGF-1R). Reduced expression of IGF-1 has been reported to cause deafness, mental retardation, postnatal growth failure, and microcephaly. IGF-1R is expressed in the retina and photoreceptor neurons; however, its functional role is not known. Global IGF-1 KO mice have age-related vision loss. We determined that conditional deletion of IGF-1R in photoreceptors and pan-retinal cells produces age-related visual function loss and retinal degeneration. Retinal pigment epithelial cell-secreted IGF-1 may be a source for IGF-1R activation in the retina. Altered retinal, fatty acid, and phosphoinositide metabolism are observed in photoreceptor and retinal cells lacking IGF-1R. Our results suggest that the IGF-1R pathway is indispensable for photoreceptor survival, and activation of IGF-1R may be an essential element of photoreceptor and retinal neuroprotection.
