Biology subjects

Gottlieb, E.

Publications and source records attributed to Gottlieb, E..

3 recordsLinked to original sources

bioRxiv2020

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

During tumor growth - when nutrient and anabolic demands are high - autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling1. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids2-4. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

cell biology↗

bioRxiv2020

Cellular water analysis in T cells reveals a switch from metabolic water gain to water influx

Cell growth is driven by the acquisition and synthesis of dry biomass and water mass. This study examines the increase of water in T cells biomass during cell growth. We found that T cell growth is initiated by a phase of slow increase of cellular water, followed by a second phase of rapid increase in water content. To study the origin of the water gain, we developed a novel method, Cold Aqua Trap - Isotope Ratio Mass Spectrometry (CAT-IRMS), which allows analysis of intracellular water isotope composition. Applying CAT-IRMS, we discovered that glycolysis-coupled metabolic water accounts on average for 11 femtoliter (fL) out of the 20 fL of water gained per cell during the slow phase. At the end of the rapid phase, before initiation of cell division, a water influx occurs, increasing the water level by three-fold. Thus, activated T cells switch from acquiring metabolic water to incorporating water from the extracellular medium. Our work provides a method to analyze cell water content and an insight into the way cells regulate their water mass.

biochemistry↗

bioRxiv2020

Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest

Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions including chronic obstructive pulmonary disease (COPD). However, the influence of SOR on T cell protective immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells. We find that low oxygen diminishes CD8+ T cell viral response in vivo. Using genetic and pharmacological models, we demonstrate that respiratory restriction inhibits ATP dependent matrix processes, all critical for mitochondrial biogenesis. The effect mediated by respiratory restriction could be rescued by TCA cycle re-stimulation, which led to increased mitochondrial matrix localized ATP via substrate-level phosphorylation. Finally, we demonstrate that short exposure to atmospheric oxygen pressure rescues the CD8+ viral response under systemic oxygen restriction in vivo. Our findings reveal the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells and provide a new approach for reducing viral infections in COPD. HighlightsO_LISystemic chronic hypoxia compromises CD8+ T cell activation C_LIO_LIShortly upon activation, T cells cytoplasmic activity becomes independent of mitochondrial ATP outflux C_LIO_LIRespiratory-blockade arrests mitochondrial remodeling due to energy depletion C_LIO_LIUncoupler-based TCA stimulation rescues respiratory-restricted activated CD8+ T cells by stimulating matrix localized substrate-level phosphorylation C_LIO_LICD8+ T cell arrest due to hypoxia in vivo can be rescued by short exposure to atmospheric oxygen pressure. C_LI

immunology↗