Developmental changes in hypoxic exposure and responses to anoxia in <i>Drosophila melanogaster</i>

Callier, Viviane; Hand, Steven C.; Campbell, Jacob B.; Biddulph, Taylor; Harrison, Jon F.

doi:10.1242/jeb.125849

Cited by 70 publications

(73 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a clear link, however, between disruption of mitochondrial metabolism and L-2HG production, as hypoxia, activation of HIFα signaling (21), disruption of the electron transport chain, and defects in citrate transport result in elevated L-2HG synthesis (17,(20)(21)(22)(23). Although our study demonstrates that flies can generate L-2HG under normoxic conditions, larvae likely experience regular bouts of hypoxia, both while immersed in their food and as a direct result of rapidly increasing body size (33). Furthermore, dERR is both required for the hypoxia response in larvae and physically interacts with HIF1α (34), indicating that larval metabolism is acutely prepared to deal with a low-oxygen environment.…”

Section: Resultsmentioning

confidence: 65%

Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

Chawla

Hurlburt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification, and cell differentiation. However, despite the ability of L-2HG to interfere with a broad range of cellular processes, this molecule is often characterized as a metabolic waste product. Here, we demonstrate that Drosophila larvae use the metabolic conditions established by aerobic glycolysis to both synthesize and accumulate high concentrations of L-2HG during normal developmental growth. A majority of the larval L-2HG pool is derived from glucose and dependent on the Drosophila estrogen-related receptor (dERR), which promotes L-2HG synthesis by up-regulating expression of the Drosophila homolog of lactate dehydrogenase (dLdh). We also show that dLDH is both necessary and sufficient for directly synthesizing L-2HG and the Drosophila homolog of L-2-hydroxyglutarate dehydrogenase (dL2HGDH), which encodes the enzyme that breaks down L-2HG, is required for stage-specific degradation of the L-2HG pool. In addition, dLDH also indirectly promotes L-2HG accumulation via synthesis of lactate, which activates a metabolic feedforward mechanism that inhibits dL2HGDH activity and stabilizes L-2HG levels. Finally, we use a genetic approach to demonstrate that dLDH and L-2HG influence position effect variegation and DNA methylation, suggesting that this compound serves to coordinate glycolytic flux with epigenetic modifications. Overall, our studies demonstrate that growing animal tissues synthesize L-2HG in a controlled manner, reveal a mechanism that coordinates glucose catabolism with L-2HG synthesis, and establish the fly as a unique model system for studying the endogenous functions of L-2HG during cell growth and proliferation.ne of the hallmarks of cancer is a dramatic reprograming of cellular metabolism that results in enhanced biosynthesis (1). These metabolic changes are particularly apparent in tumors that use the Warburg effect, also referred to as aerobic glycolysis, a metabolic program characterized by elevated levels of glucose consumption and enhanced lactate production (1, 2). By activating aerobic glycolysis, tumors are able to synthesize macromolecules rapidly from glycolytic intermediates. In addition, elevated levels of lactate dehydrogenase (LDH) activity allow proliferating cells to synthesize lactate and maintain the NAD + levels required for high rates of glucose catabolism and biomass production (1).The metabolic reprogramming of cancer cells, however, extends beyond biosynthesis, as many tumors also generate progrowth metabolites, or oncometabolites, that promote tumor formation via nonmetabolic means. Most notable among these compounds is D-2-hydroxyglutarate (D-2HG), which is associated with cancers such as gliomas and acute myelogenous leukemias (3). Although D-2HG is generated as a normal byproduct of γ-hydroxybutyrate metabolism (4), oncogenic D-2HG production is the result of neomorphic mutations in the active site of isocitrate dehydrogenas...

show abstract

Section: Resultsmentioning

confidence: 65%

Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

Chawla

Hurlburt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Although research has focused on a few species, which often reside in oxygen-rich environments, many animals live in soils that become hypoxic [69]. Some insects pass through larval stages that experience periods of hypoxia in rotting fruit, meat, or feces [70]. Other insects pass through aquatic stages before becoming terrestrial adults.…”

Section: Discussionmentioning

confidence: 99%

More oxygen during development enhanced flight performance but not thermal tolerance of Drosophila melanogaster

et al. 2017

View full text Add to dashboard Cite

High temperatures can stress animals by raising the oxygen demand above the oxygen supply. Consequently, animals under hypoxia could be more sensitive to heating than those exposed to normoxia. Although support for this model has been limited to aquatic animals, oxygen supply might limit the heat tolerance of terrestrial animals during energetically demanding activities. We evaluated this model by studying the flight performance and heat tolerance of flies (Drosophila melanogaster) acclimated and tested at different concentrations of oxygen (12%, 21%, and 31%). We expected that flies raised at hypoxia would develop into adults that were more likely to fly under hypoxia than would flies raised at normoxia or hyperoxia. We also expected flies to benefit from greater oxygen supply during testing. These effects should have been most pronounced at high temperatures, which impair locomotor performance. Contrary to our expectations, we found little evidence that flies raised at hypoxia flew better when tested at hypoxia or tolerated extreme heat better than did flies raised at normoxia or hyperoxia. Instead, flies raised at higher oxygen levels performed better at all body temperatures and oxygen concentrations. Moreover, oxygen supply during testing had the greatest effect on flight performance at low temperature, rather than high temperature. Our results poorly support the hypothesis that oxygen supply limits performance at high temperatures, but do support the idea that hyperoxia during development improves performance of flies later in life.

show abstract

“…Replicated groups (15-25 flies per group, n = 3 ~ 7) of flies were examined. We chose the anoxia exposure of 1, 3, or 6 h because flies are highly tolerant to anoxia for hours [20].…”

Section: Post-anoxia Survivalmentioning

confidence: 99%

Drosophilaegg-derived tyrosine phosphatase (EDTP): a novel target for improved survivorship to prolonged anoxia and cellular protein aggregates

Xiao

Qiu

et al. 2018

Preprint

View full text Add to dashboard Cite

Drosophila egg-derived tyrosine phosphatase (EDTP), a lipid phosphatase that removes 3position phosphate at the inositol ring, has dual functions in the oogenesis and the muscle performance during adult stages. A mammalian homologous gene MTMR14, which encodes the myotubularin-related protein 14, negatively regulates autophagy. Mutation of EDTP/MTMR14, however, causes at least three deleterious consequences: (1) lethality in the early embryogenesis in Drosophila; (2) "jumpy" phenotype with apparently impaired motor functions; and (3) association with a rare genetic disorder called centronuclear myopathy. Here we show that flies carrying a heterozygous EDTP mutation had increased survivorship to prolonged anoxia; tissuespecific downregulation of EDTP in non-muscle tissues, particularly motoneurons, extended the lifespan; and tissue-specific downregulation of EDTP in motoneurons improved the survivorship to beta-amyloid peptides (Aβ42) and polyglutamine (polyQ) protein aggregates. MTMR14 expression was evident in the hippocampus and cortex in C57BL/6J and APP/PS1 mice.Compared with C57BL/6J mice, APP/PS1 mice had reduced MTMR14 in the cortex but not in the hippocampus. Hippocampal expression of MTMR14 was increased and plateaued at 9-17 months compared with 2-6 months in C57BL/6J mice. Aβ42 treatment increased the expression of MTMR14 in the primarily cultured hippocampal neurons of Sprague/Dawley rats and mouse Neuro2a neuroblasts. We demonstrated a novel approach of tissue-specific manipulation of the disease-associated gene EDTP/MTMR14 for lifespan extension and the improvement of survivorship to cellular protein aggregates.

show abstract

Developmental changes in hypoxic exposure and responses to anoxia in Drosophila melanogaster

Cited by 70 publications

References 55 publications

Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

More oxygen during development enhanced flight performance but not thermal tolerance of Drosophila melanogaster

Drosophilaegg-derived tyrosine phosphatase (EDTP): a novel target for improved survivorship to prolonged anoxia and cellular protein aggregates

Contact Info

Product

Resources

About