PhotoEnergy

Investigating possible links between photoreceptor cGMP-signaling and energy metabolism

01.10.2022 bis 30.06.2024

The retina is the neuronal tissue with the highest energy demand (Country, 2017, Wong-Riley, 2010). Paradoxically, the mammalian retina has been suggested to strongly rely on energy-inefficient glycolysis, even though oxygen and high energy yield oxidative phosphorylation (OXPHOS) are available (Winkler, 1981). This so called “aerobic glycolysis” releases large amounts of lactate, as already reported in the 1920s by Otto Warburg (Warburg, 1925). High retinal energy demand is linked to the extraordinary single-photon sensitivity of photoreceptors (Wong-Riley, 2010, Okawa et al., 2008, Ames, 1992a), as well as to lipid synthesis for the constant renewal of photoreceptor outer segments (Chinchore et al., 2017, Young, 1967).
Our previous work showed that cGMP-signaling plays a crucial role for photoreceptor degeneration in hereditary retinal degeneration (RD) (Vighi et al., 2018). High levels of cGMP activate protein kinase G (PKG), a main effector of cGMP-signaling. We found that activation of PKG is necessary and sufficient to produce photoreceptor cell death (Paquet-Durand et al., 2009). however, at present it is still unclear how exactly PKG can cause cell death. Very recently, we could show that PKG acts upon proteins that regulate or otherwise influence energy metabolism (Roy et al., 2021, Roy et al., 2022). These proteins include 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key regulator of energy metabolism that can switch energy production from OXPHOS to glycolysis. Thus, a PKG-dependent regulation of PFKFB3 could have a strong influence on energy production. Other PKG targets with a bearing on energy metabolism are Kv1-type K+ channels. The K+-outflow mediated by Kv1 channels must be counterbalanced by the ATP-driven Na+/K+ exchanger (NKX), which in photoreceptors is responsible for 50-75% of total ATP-expenditure (Ames, 1992b, Okawa et al., 2008). Hence, a regulation of Kv1 channel activity by PKG could have a large impact on overall photoreceptor energy consumption.
Here, we want to investigate the possible links between cGMP-signaling and energy metabolism using organotypic retinal explant cultures subjected to manipulations of energy producing pathways. Readouts will include metabolomic analysis, enzyme expression studies, as well as markers for cell death.