Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

Abstract

Vision commences in the retina with rod and cone photoreceptors that detect and convert light to electrical signals. The irreversible loss of photoreceptors due to neurodegenerative disease leads to visual impairment and blindness. Interventions now in development include transplanting photoreceptors, committed photoreceptor precursors, or retinal pigment epithelial (RPE) cells, with the latter protecting photoreceptors from dying. However, introducing exogenous human cells in a clinical setting faces both regulatory and supply chain hurdles. Recent work has shown that abnormalities in central cell metabolism pathways are an underlying feature of most neurodegenerative disorders, including those in the retina. Reversal of key metabolic alterations to drive retinal repair thus represents a novel strategy to treat vision loss based on cell regeneration. Here, we review the connection between photoreceptor degeneration and alterations in cell metabolism, along with new insights into how metabolic reprogramming drives both retinal development and repair following damage. The potential impact of metabolic reprogramming on retinal regeneration is also discussed, specifically in the context of how metabolic switches drive both retinal development and the activation of retinal glial cells known as Müller glia. Müller glia display latent regenerative properties in teleost fish, however, their capacity to regenerate new photoreceptors has been lost in mammals. Thus, re-activating the regenerative properties of Müller glia in mammals represents an exciting new area that integrates research into developmental cues, central metabolism, disease mechanisms, and glial cell biology. In addition, we discuss this work in relation to the latest insights gleaned from other tissues (brain, muscle) and regenerative species (zebrafish).

Complex II ambiguities—FADH2 in the electron transfer system

“…C , from ambiguous NADH-FADH 2 analogy ( 73 ) to ( D ) graphical misconception ( 58 ), as in ref. ( 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 ...…”

“…5 S ), with a similar misconception or ambiguity in figures of refs. ( 129 , 166 , 171 , 176 , 183 , 223 , 241 , 339 , 373 ) ( Table 2 ). Electron transfer is even shown to proceed from fatty acids through ETF to CII ( 350 , 351 ) ( Fig.…”

Identification of Human Retinal Organoid Cell Differentiation-Related Genes via Single-Cell Sequencing Data Analysis

“…Phototransduction is a biological process of photoreceptor cells to transform the optical signal into an electrical signal. Opsins in photoreceptor cells can form photoreceptors with chromophore [ 37 ]. NRL and NR2E3 in Cluster 1 are pertinent to degenerative retina diseases.…”

Glycolytic flux controls retinal progenitor cell differentiation via regulating Wnt signaling

“…Cellular energy and precursor metabolites are produced by the metabolism of glucose, which is converted into pyruvate via glycolysis. Glycolysis is a multi-step enzymatic process that occurs in the cytosol, does not require O2, and produces 2 molecules of ATP per glucose molecule (Hanna et al, 2022). Pyruvate is either transported to mitochondria for further oxidation to drive oxidative phosphorylation (OXPHOS) by the electron transport chain, or converted to lactate and secreted out of the cell.…”

“…Pyruvate is either transported to mitochondria for further oxidation to drive oxidative phosphorylation (OXPHOS) by the electron transport chain, or converted to lactate and secreted out of the cell. OXPHOS is an O2-dependent metabolic pathway that produces 30-38 ATP molecules for each glucose molecule, and hence, produces more cellular energy than glycolysis (Hanna et al, 2022). Yet, the majority of vertebrate retinal cells rely on glycolysis as the main metabolic pathway, even in the presence of O2 (Hurley et al, 2015).…”