The oncometabolite L-2-hydroxyglutarate is a common product of dipteran larval development

Mahmoudzadeh, Nader H.; Fitt, Alexander J; Schwab, Daniel B.; Martenis, William E.; Nease, Lauren M.; Owings, Charity G.; Brinkley, Garrett J.; Li, Hongde; Karty, Jonathan A.; Sudarshan, Sunil; Hardy, Richard W.; Moczek, Armin P.; Picard, Christine; Tennessen, Jason M.

doi:10.1016/j.ibmb.2020.103493

Cited by 9 publications

(17 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 ), the observed increases in succinate, fumarate, and malate hint at the possibility that maternal–zygotic mutants exhibit significant changes in mitochondrial metabolism. However, since we observe no changes in the relative abundance of alanine, lactate, and 2-hydroxyglutarate, which are commonly elevated in flies that experience disruption of mitochondrial activity ( Feala et al 2007 ; Coquin et al 2008 ; Campbell et al 2019 ; Mahmoudzadeh et al 2020 ), the significance of these changes in Gpdh1 maternal–zygotic mutant remain unclear. One explanation is that these metabolomic results hint at a role for maternal GPDH1 that is distinguishable from the zygotic GPDH1 pool.…”

Section: Discussionmentioning

confidence: 67%

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

Rai

Carter

Shefali

et al. 2022

G3 Genes|Genomes|Genetics

Self Cite

View full text Add to dashboard Cite

As the fruit fly, Drosophila melanogaster, progresses from one life stage to the next, many of the enzymes that compose intermediary metabolism undergo substantial changes in both expression and activity. These predictable shifts in metabolic flux allow the fly meet stage-specific requirements for energy production and biosynthesis. In this regard, the enzyme Glycerol-3-phosphate dehydrogenase (GPDH1) has been the focus of biochemical genetics studies for several decades, and as a result, is one of the most well-characterized Drosophila enzymes. Among the findings of these earlier studies is that GPDH1 acts throughout the fly lifecycle to promote mitochondrial energy production and triglyceride accumulation while also serving a key role in maintaining redox balance. Here we expand upon the known roles of GPDH1 during fly development by examining how depletion of both the maternal and zygotic pools of this enzyme influences development, metabolism, and viability. Our findings not only confirm previous observations that Gpdh1 mutants exhibit defects in larval development, lifespan, and fat storage but also reveal that GPDH1 serves essential roles in oogenesis and embryogenesis. Moreover, metabolomics analysis reveals that a Gpdh1 mutant stock maintained in a homozygous state exhibits larval metabolic defects that significantly differ from those observed in the F1 mutant generation. Overall, our findings highlight unappreciated roles for GPDH1 in early development and uncover previously undescribed metabolic adaptations that could allow flies to survive loss of this key enzyme.

show abstract

Section: Discussionmentioning

confidence: 67%

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

Rai

Carter

Shefali

et al. 2022

G3 Genes|Genomes|Genetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…The copyright holder for this preprint this version posted February 16, 2022. ; https://doi.org/10.1101/2022.02.15.480380 doi: bioRxiv preprint mitochondria for ATP production (Figure 1), the observed increases in succinate, fumarate, and malate hint at the possibility that maternal-zygotic mutants exhibit significant changes in mitochondrial metabolism. However, since we observe no changes in the relative abundance of alanine, lactate, and 2-hydroxyglutarate, which are commonly elevated in flies that experience disruption of mitochondrial activity (FEALA et al 2007;COQUIN et al 2008;CAMPBELL et al 2019;MAHMOUDZADEH et al 2020), the significance of these changes in Gpdh1 maternal-zygotic mutant remain unclear.…”

Section: Discussionmentioning

confidence: 69%

“…2008; C ampbell et al . 2019; M ahmoudzadeh et al . 2020), the significance of these changes in Gpdh1 maternal-zygotic mutant remain unclear.…”

Section: Discussionmentioning

confidence: 99%

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

Rai

Carter

Shefali

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

As the fruit fly, Drosophila melanogaster, progresses from one life stage to the next, many of the enzymes that compose intermediary metabolism undergo substantial changes in both expression and activity. These predictable shifts in metabolic flux allow the fly meet stage-specific requirements for energy production and biosynthesis. In this regard, the enzyme Glyerol-3-phosphate dehydrogenase (GPDH1) has been the focus of biochemical genetics studies for several decades, and as a result, is one of the most well characterized Drosophila enzymes. Among the findings of these earlier studies is that GPDH1 acts throughout the fly lifecycle to promote mitochondrial energy production and triglyceride accumulation while also serving a key role in maintaining redox balance. Here we expand upon the known roles of GPDH1 during fly development by examining how depletion of both the maternal and zygotic pools of this enzyme influences development, metabolism, and viability. Our findings not only confirm previous observations that Gpdh1 mutants exhibit defects in larval development, lifespan, and fat storage but also reveal that GPDH1 serves essential roles in oogenesis and embryogenesis. Moreover, metabolomics analysis reveals that a Gpdh1 mutant stock maintained in a homozygous state exhibits larval metabolic defects that significantly differ from those observed in the F1 mutant generation. Overall, our findings highlight unappreciated roles for GPDH1 in early development and uncover previously undescribed metabolic adaptations that could allow flies to survive loss of this key enzyme.

show abstract

“…One caveat with these findings is that our method of 2HG detection included both L-2HG and D-2HG. Although D- and L-2HG are present at similar levels in adults [113], the two enantiomers are produced by distinct enzymatic mechanisms. Since dLdh expression is elevated in aging brains and glial dLdh upregulation drives a dramatic increase in 2HG levels, our findings are likely attributable to L-2HG accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…Since dLdh expression is elevated in aging brains and glial dLdh upregulation drives a dramatic increase in 2HG levels, our findings are likely attributable to L-2HG accumulation. In the past, L-2HG has only been found to increase to appreciable levels in the adult brain of D. melanogaster through an ATF4-dependent unfolded protein response when mitochondrial stress is induced [116], or in flies exposed to hypoxic conditions [113]. Therefore, aging may cause accumulation of L-2HG due to a change in brain metabolism reminiscent of responses to mitochondrial stress or hypoxia, and these metabolic pathways may be further activated in the brains of glial dLdh upregulation flies due to elevated lactate accumulation.…”

Section: Discussionmentioning

confidence: 99%

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

Frame

Robinson

Mahmoudzadeh

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression ofDrosophila melanogasterlactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.Author SummaryThe brain is composed of metabolically demanding cell types that must remain functional throughout life to maintain cognitive tasks like memory formation. How brain metabolism varies between cell-types across the lifespan is uncertain. It has been suggested that in vertebrate brains glia breakdown sugars to produce lactate and shuttle it to neurons to support long-term memory and survival. Yet, this phenomenon has not been directly tested in invertebrates. InDrosophila melanogasterflies, we genetically manipulated lactate dehydrogenase, a central enzyme in lactate metabolism, specifically within the adult brain. We discovered that shifting lactate metabolism to either higher or lower levels in neurons caused decreased survival and worse long-term memory with age. In contrast, we found increased glial lactate metabolism worsened survival, whereas decreased glial lactate metabolism impaired long-term memory in aged flies. Both increased glial or neuronal lactate metabolism led to increased accumulation of metabolites, such as 2-hydroxyglutarate, mitochondrial metabolites, and neutral lipids, in aged fly brains. These findings provide evidence for the first time in invertebrates that lactate and memory are connected and altered lactate metabolism in neurons and glia differentially impact survival and memory, but only in an age-dependent manner.Graphical Abstract

show abstract

The oncometabolite L-2-hydroxyglutarate is a common product of dipteran larval development

Cited by 9 publications

References 38 publications

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

Contact Info

Product

Resources

About