Biology subjects

Moore, T. I.

Publications and source records attributed to Moore, T. I..

4 recordsLinked to original sources

bioRxiv2025

Glycosphingolipids Regulate Phosphatidylserine Transport at ER-PM Contact Sites

Plasma membrane (PM) localization of KRAS requires specific glycosphingolipids in the outer leaflet and phosphatidylserine (PS) in the inner leaflet. PM PS content is controlled by lipid transport proteins ORP5 and ORP8, which operate at ER-PM membrane contact sites (MCSs). Using high-resolution imaging, we now show that GSLs including GM3 and SM4, are required to maintain ORP5 and ORP8 localization to MCSs. Genetic deletion or pharmacologic inhibition of enzymes required for the biosynthesis of GM3 or SM4, displace PI4-kinase Type III (PI4KIII) and its adaptor EFR3A from the PM, thereby reducing PM phosphatidylinositol 4-phosphate (PI4P) content. PM interactions of ORP5 and ORP8 are also disrupted. Since ORP5 and ORP8 transport PS to the PM by counter-transporting PI4P to the ER, PM PS content is substantially reduced. We further show that GM3 and GM2 regulate the assembly of ER-PM-MCSs, such that the function of other MCS-localized macromolecular machineries including calcium release-activated calcium channels is abrogated when glycosphingolipid biosynthesis is blocked. Together, this study establishes glycosphingolipids as organizers of PS transport and ER-PM MCSs, expanding the regulators of MCSs beyond protein tethers to include glycosylated lipids and revealing how glycosphingolipids control KRAS function.

molecular biology↗

bioRxiv2025

Background color matching influences sexual behavior, growth, and mortality rate in an African cichlid fish

Phenotypic plasticity allows organisms to adapt to changing environments within their lifetimes. The cost of plastic adaptations may constrain the persistence of plasticity over evolutionary time. One potential cost is the possibility that phenotypic adjustment to specific environments can cause correlated responses that are not necessarily adaptive. Males in the African cichlid Astatotilapia burtoni are blue or yellow, and males are able adjust their body coloration to the color of the background, presumably to increase crypsis. To test whether background color influences fitness-related traits, we raised mix-sex groups of juvenile A. burtoni to adulthood in yellow or blue tanks. We found that fish in blue tanks were darker and more bluish, whereas fish reared in yellow tanks were paler and more yellow in body coloration. Males, but not females, from blue tanks showed earlier sexual maturation than those held in yellow tanks. However, across the duration of the experiment, there was a higher frequency of females mouthbrooding in groups housed in yellow tanks than those that were housed in blue tanks. In addition, fish in blue tanks exhibited reduced growth rate but higher survivorship relative to their yellow-reared counterparts. Our data suggests that background color affects important fitness-related traits in a color polymorphic cichlid, which may influence the evolution of phenotypic plasticity.

animal behavior and cognition↗

bioRxiv2024

Intracellular Lactate Dynamics Reveal the Metabolic Diversity of Drosophila Glutamatergic Neurons

Rates of lactate production and consumption reflect the metabolic state of many cell types, including neurons. Here, we investigate the effects of nutrient deprivation on lactate dynamics in Drosophila glutamatergic neurons by leveraging the limiting effects of the diffusion barrier surrounding cells in culture. We found that neurons constitutively consume lactate when availability of trehalose, the glucose disaccharide preferred by insects, is limited by the diffusion barrier. Acute mechanical disruption of the barrier reduced this reliance on lactate. Through kinetic modeling and experimental validation, we demonstrate that neuronal lactate consumption rates correlate inversely with their mitochondrial density. Further, we found that lactate levels in neurons exhibited temporal correlations that allowed prediction of cytosolic lactate dynamics after the disruption of the diffusion barrier from pre-perturbation lactate fluctuations. Collectively, our findings reveal the influence of diffusion barriers on neuronal metabolic preferences, and demonstrate the existence of temporal correlations between lactate dynamics under conditions of nutrient deprivation and those evoked by the subsequent restoration of nutrient availability.

neuroscience↗

bioRxiv2023

Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis

Maintaining protein homeostasis is essential for cellular health. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response, activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2 signaling pathway, increasing phosphorylation of eIF2 and improving the ERs ability to handle proteostasis. MERSR activation in both polyglutamine and amyloid-beta peptide-expressing C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.

cell biology↗