Biology subjects

Tennessen, J. M.

Publications and source records attributed to Tennessen, J. M..

At least 19 recordsLinked to original sources

bioRxiv2026

Structural modeling supports an interaction between the Drosophila Estrogen-Related Receptor and Sima/HIF-1α

The Drosophila Estrogen-Related Receptor (dERR) is an orphan nuclear receptor that regulates developmental metabolism, yet the protein cofactors that modulate its activity remain poorly defined. Here, we used the AI-based FlyPredictome platform to identify candidate dERR interaction partners and evaluate their predicted structural interfaces. Among the highest-confidence interactors is the transcription factor Sima, which represents the Drosophila ortholog of HIF1 - an interaction that was reciprocally identified in both dERR and Sima/HIF1 interaction datasets. Structural modeling predicted binding between the dERR ligand-binding domain and a conserved LXXLL motif in Sima/HIF1. Notably, the predicted dERR- Sima/HIF1 interaction interface includes residues previously shown to be essential for in vitro binding, providing independent structural support for this biologically relevant protein-protein interaction.

developmental biology↗

bioRxiv2026

Exposure to perfluorooctanoic acid accelerates Drosophila melanogaster juvenile development and disrupts mitochondrial metabolism

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants with poorly understood sublethal effects on insects. Perfluorooctanoic acid (PFOA), one of the most widely distributed legacy PFAS is increasingly recognized for altering organismal physiology beyond traditional toxicity endpoints. Here, we use the fruit fly Drosophila melanogaster as a model to examine how PFOA exposure during larval (juvenile) development reshapes insect life-history progression and metabolic homeostasis. Our studies reveal that at environmentally relevant concentrations (nM to low {micro}M), PFOA induces precocious expression of developmentally-regulated genes and leads to metabolic changes that persist into adulthood. At higher concentrations used to probe mechanism, PFOA accelerates larval development, disrupts mitochondrial membrane potential, and increases whole-organism metabolic heat production - results that suggest altered mitochondrial energetic efficiency. Consistent with this tradeoff, PFOA-exposed larvae that develop faster under permissive conditions exhibit heightened sensitivity to environmental stressors, including elevated temperature and reduced food hydration. Together, these findings demonstrate that PFOA disrupts metabolic and developmental processes in a dose- and context-dependent manner, highlighting sublethal effects that may influence insect resilience under environmental stress. SYNOPSIS STATEMENTHere we describe how PFOA alters the growth, development, and metabolism of the fruit fly Drosophila melanogaster. Specifically, we find that PFOA accelerates Drosophila juvenile growth while also rendering exposed larvae sensitive to environmental stress. These observations suggest that widespread PFOA contamination may impair the developmental fitness of insect populations.

pharmacology and toxicology↗

bioRxiv2026

Conserved Molecular Responses to Arsenite Exposure in Drosophila melanogaster

Arsenic exposure is a pervasive global health threat strongly associated with increased risk of morbidities such as diabetes, cardiovascular disease, and cancer. Despite extensive studies describing the dangers of arsenic exposure, the molecular initiating events that link arsenic to chronic disease onset and progression remain poorly defined. To address this knowledge gap, we combined time-resolved transcriptomic and metabolomic profiling of adult Drosophila melanogaster exposed to sodium (meta) arsenite (NaAsO2). We uncovered coordinated, dose-dependent shifts in gene expression and metabolite abundance that activate canonical detoxification pathways and mirror arsenic-associated disease signatures in humans. Notably, flies rapidly upregulated heatshock and xenobiotic response gene networks, followed by biomarkers characteristic of diabetic states (elevated glucose, lactate, and methylglyoxal, for example). These findings reveal conserved molecular pathways that couple arsenic exposure to metabolic dysfunction and establish Drosophila as a powerful whole-organism model for identifying early biomarkers and mechanistic drivers of arsenic-induced disease phenotypes.

pharmacology and toxicology↗

bioRxiv2025

NAD+ reduction in glutamatergic neurons triggers fatty acid catabolism and neuroinflammation in the brain, mitigated by SARM1 deletion

The importance of NAD+ homeostasis for neuronal health has been emphasized by studies on nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2), a NAD+-synthesizing enzyme, and sterile alpha and TIR motif-containing protein 1 (SARM1), a NAD+ hydrolase. NMNAT2 declines caused by neurodegenerative insults activate SARM1 to degenerate axons. To elucidate the impact of the NMNAT2-SARM1 axis on brain energy metabolism, we employed multi-omics approaches to investigate the metabolic effects caused by neuronal NMNAT2 loss. The loss of NMNAT2 in glutamatergic neurons results in a striking metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes. Proteomic analysis found that neuronal NMNAT2 loss altered levels of glial enzymes central to glucose and lipid metabolism. Genetic deletion of SARM1 in NMNAT2-deficient mice restores lipid metabolism and mitigates neurodegeneration. Taken together, we show that neuronal NAD+ reduction leads to SARM1-dependent maladaptive adaptations in both neurons and glia.

neuroscience↗

bioRxiv2025

The alternative oxidase reconfigures the larval mitochondrial electron transport system to accelerate growth and development in Drosophila melanogaster

The alternative oxidase (AOX) is naturally present in the mitochondrial electron transfer system (ETS) of many organisms but absent in vertebrates and most insects. AOX oxidizes coenzyme Q and reduces O2 in H2O, partially replacing the ETS cytochrome c segment and alleviating the oxidative stress caused by ETS overload. As successfully demonstrated in animal models, AOX shows potential in mitigating mitochondrial diseases. However, its non-proton-pumping nature may uncouple mitochondria, leading to excessive heat generation and interference with normal metabolism and physiology. Here we show that AOX from the tunicate Ciona intestinalis accelerates development of Drosophila melanogaster, elevating larval biomass accumulation (primarily due to increased fat), mobility and food intake, without increasing body heat production. AOX intensifies Leak respiration and lowers oxidative phosphorylation efficiency through functional interactions with the mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH). This is associated with increased complex I (CI)-driven respiration and supercomplex formation, higher cellular NAD+/NADH ratios, and an enhanced flux through the central carbon metabolism. Chemical uncouplers and rotenone confirm the roles of mitochondrial uncoupling and CI in the development of AOX-expressing larvae. Thus, AOX appears to be promoting increased growth by reinforcing the larval proliferative metabolic program via an intricate mechanism that reconfigures the larval ETS.

biochemistry↗

bioRxiv2024

The Drosophila Estrogen-Related Receptor promotes triglyceride storage within the larval fat body

The Estrogen-Related Receptor (ERR) family of nuclear receptors (NRs) serve key roles in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, ERR activity promotes TAG storage during the post-embryonic growth phase, with loss-of-function mutations in mouse Esrra and Drosophila melanogaster dERR inducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation within adipose tissue remains poorly understood, as previous transcriptomic and metabolomic studies relied on whole animal analyses. Here we address this shortcoming by using tissue-specific approaches to examine the role of dERR in regulating lipid metabolism within the Drosophila larval fat body. We find that dERR autonomously promotes TAG accumulation within fat body cells and regulates expression of genes involved in glycolysis, {beta}-oxidation, and mevalonate metabolism. As an extension of these results, we not only discovered that dERR mutant fat bodies exhibit decreased expression of known dHNF4 target genes but also found that dHNF4 activity is decreased in dERR mutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with developmental growth and hint at a conserved mechanism by which ERR and HNF4 homologs coordinately regulate metabolic gene expression.

developmental biology↗

bioRxiv2024

Glycolytic Disruption Triggers Interorgan Signaling to Nonautonomously Restrict Drosophila melanogaster Larval Growth

Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate Dehydrogenase (Ldh) and Glycerol-3-phosphate dehydrogenase (Gpdh1) support larval biosynthetic metabolism by maintaining NAD+/NADH redox balance and promoting glycolytic flux. Consistent with the cooperative functions of Ldh and Gpdh1, the loss of both enzymes, but neither single enzyme, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the Gpdh1; Ldh double mutant lethal phenotype could be mediated nonautonomously. Here we find that the developmental arrest displayed by the double mutants extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, we demonstrate that this synthetic lethality is linked to the upregulation of Upd3, a cytokine involved in the Jak/Stat signaling pathway. Moreover, we demonstrate that either loss of the Upd3 or dietary administration of the steroid hormone 20-hydroxyecdysone (20E) rescue the synthetic lethal phenotype of Gpdh1; Ldh double mutants. Together, these findings demonstrate that metabolic disruptions within a single tissue can nonautonomously modulate interorgan signaling to ensure synchronous developmental growth. SUMMARY STATEMENTWe used the fruit fly Drosophila melanogaster to demonstrate that disruption of glycolysis within a single larval tissue alters systemic cytokine signaling and nonautonomously inhibits development of the entire animal.

developmental biology↗

bioRxiv2024

Exposure to the pesticide tefluthrin causes developmental neurotoxicity in zebrafish

BACKGROUNDThe insecticide tefluthrin is widely used in agriculture, resulting in widespread pollution. Tefluthrin is a type I pyrethroid characterized by its high persistence in the environment. Understanding the mechanisms of toxicity of tefluthrin will improve its risk assessment. OBJECTIVESWe aimed to decipher the molecular modes of action of tefluthrin. METHODSPhenotypic developmental toxicity was assessed by exposing zebrafish embryos and larvae to increasing concentrations of tefluthrin. Tg(mnx:mGFP) line was used to assess neurotoxicity. Multi-omics approaches including transcriptomics and lipidomics were applied to analyze RNA and lipid contents, respectively. Finally, an in-silico ligand-protein docking computational method was used to study a possible interaction between tefluthrin and a protein target. RESULTSTefluthrin exposure caused severe morphological malformations in zebrafish larvae, including motor neuron abnormalities. The differentially expressed genes were associated with neurotoxicity and metabolic disruption. Lipidomics analysis revealed a disruption in fatty acid, phospholipid, and lysophospholipid recycling. Protein docking modeling suggested that the LPCAT3 enzyme, which recycles lysophospholipids in the Lands cycle, directly interacts with tefluthrin. CONCLUSIONSTefluthrin exposure causes morphological and neuronal malformations in zebrafish larvae at nanomolar concentrations. Multi-omics results revealed a potential molecular initiating event i.e., inhibition of LPCAT3, and key events i.e., an altered lysophospholipid to phospholipid ratio, leading to the adverse outcomes of neurotoxicity and metabolic disruption.

pharmacology and toxicology↗

bioRxiv2024

Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster

The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly Drosophila melanogaster to investigate the endogenous functions of L2hgdh. Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions, L2hgdh mutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system (Malpighian tubules; MTs) is a key site of L2hgdh activity, as L2hgdh mutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions, L2hgdh mutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation. Overall, our findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.

genetics↗

bioRxiv2023

Auxin Exposure Disrupts Feeding Behavior and Fatty Acid Metabolism in Adult Drosophila

The ease of genetic manipulation in Drosophila melanogaster using the Gal4/UAS system has been beneficial in addressing key biological questions. Current modifications of this methodology to temporally induce transgene expression require temperature changes or exposure to exogenous compounds, both of which have been shown to have detrimental effects on physiological processes. The recently described auxin-inducible gene expression system (AGES) utilizes the plant hormone auxin to induce transgene expression and is proposed to be the least toxic compound for genetic manipulation, with no obvious effects on Drosophila development and survival in one wild-type strain. Here we show that auxin delays larval development in another widely-used fly strain, and that short- and long-term auxin exposure in adult Drosophila induces observable changes in physiology and feeding behavior. We further reveal a dosage response to adult survival upon auxin exposure, and that the recommended auxin concentration for AGES alters feeding activity. Furthermore, auxin fed male and female flies exhibit a significant decrease in triglyceride levels and display altered transcription of fatty acid metabolism genes. Although fatty acid metabolism is disrupted, auxin does not significantly impact adult female fecundity or progeny survival, suggesting AGES may be an ideal methodology for studying limited biological processes. These results emphasize that experiments using temporal binary systems must be carefully designed and controlled to avoid confounding effects and misinterpretation of results.

physiology↗

bioRxiv2023

Characterization of genetic and molecular tools for studying the endogenous expression of Lactate dehydrogenase in Drosophila melanogaster

Drosophila melanogaster larval development relies on a specialized metabolic state that utilizes carbohydrates and other dietary nutrients to promote rapid growth. One unique feature of the larval metabolic program is that Lactate Dehydrogenase (Ldh) activity is highly elevated during this growth phase when compared to other stages of the fly life cycle, indicating that Ldh serves a key role in promoting juvenile development. Previous studies of larval Ldh activity have largely focused on the function of this enzyme at the whole animal level, however, Ldh expression varies significantly among larval tissues, raising the question of how this enzyme promotes tissue-specific growth programs. Here we characterize two transgene reporters and an antibody that can be used to study Ldh expression in vivo. We find that all three tools produce similar Ldh expression patterns. Moreover, these reagents demonstrate that the larval Ldh expression pattern is complex, suggesting the purpose of this enzyme varies across cell types. Overall, our studies validate a series of genetic and molecular reagents that can be used to study glycolytic metabolism in the fly.

developmental biology↗

bioRxiv2023

Metabolomic analysis of Drosophila melanogaster larvae lacking Pyruvate kinase

Pyruvate kinase (Pyk) is a rate-limiting enzyme that catalyzes the final metabolic reaction in glycolysis. The importance of this enzyme, however, extends far beyond ATP production, as Pyk is also known to regulate tissue growth, cell proliferation, and development. Studies of this enzyme in Drosophila melanogaster, however, are complicated by the fact that the fly genome encodes six Pyk paralogs whose functions remain poorly defined. To address this issue, we used sequence distance and phylogenetic approaches to demonstrate that the gene Pyk encodes the enzyme most similar to the mammalian Pyk orthologs, while the other five Drosophila Pyk paralogs have significantly diverged from the canonical enzyme. Consistent with this observation, metabolomic studies of two different Pyk mutant backgrounds revealed that larvae lacking Pyk exhibit a severe block in glycolysis, with a buildup of glycolytic intermediates upstream of pyruvate. However, our analysis also unexpectedly reveals that steady state pyruvate levels are unchanged in Pyk mutants, indicating that larval metabolism maintains pyruvate pool size despite severe metabolic limitations. Consistent with our metabolomic findings, a complementary RNA-seq analysis revealed that genes involved in lipid metabolism and peptidase activity are elevated in Pyk mutants, again indicating that loss of this glycolytic enzyme induces compensatory changes in other aspects of metabolism. Overall, our study provides both insight into how Drosophila larval metabolism adapts to disruption of glycolytic metabolism as well as immediate clinical relevance, considering that Pyk deficiency is the most common congenital enzymatic defect in humans.

developmental biology↗

bioRxiv2023

The herbicide acetochlor causes lipid peroxidation by inhibition of glutathione peroxidase 4

Obesity is increasing worldwide, particularly in rural communities, where people are likely exposed to high levels of pesticides. We here investigated whether six commonly used agricultural pesticides on corn and soy fields have adipogenic activity and act as obesogens. Exposure to two pesticides, the herbicides acetochlor and metolachlor, induced adipogenesis in vitro in mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure caused morphological malformations and lethality in zebrafish larvae with an EC50 of 7.8 {micro}M and an LC50 of 12 {micro}M. Acetochlor exposure also resulted in lipid accumulation is zebrafish larvae when simultaneously fed a high cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we preformed transcriptomic and targeted lipidomic analysis of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consequently, Gpx4 activity was efficiently repressed by acetochlor, and lipid peroxidation was increased in zebrafish. We propose that acetochlor disrupts lipid homeostasis by inhibiting Gpx4, resulting in accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species in the cells, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contain the chloroacetamide group, inhibition of Gpx4 activity may represent a novel, common molecular initiating event of obesogens. SynopsisRural populations have a high prevalence of metabolic disease and are highly exposed to pesticides. This study reports that the herbicide acetochlor, heavily used on soy and corn fields, inhibits an enzyme that protects from oxidation of lipids in the cell membrane, oxidative stress and a type of cell death called ferroptosis, features that are linked to metabolic disruption and obesity.

pharmacology and toxicology↗

bioRxiv2022

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

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 of Drosophila melanogaster lactate 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. In Drosophila melanogaster flies, 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/512981v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@6b34d7org.highwire.dtl.DTLVardef@5a159forg.highwire.dtl.DTLVardef@41a3f6org.highwire.dtl.DTLVardef@17377ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

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

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.

developmental biology↗

bioRxiv2022

A honey bee symbiont buffers larvae against nutritional stress through lysine supplementation

Honey bees, the worlds most significant agricultural pollinator, have suffered dramatic losses in the last few decades (1,2). These losses are largely due to the synergistic effects of multiple stressors, the most pervasive of which is limited nutrition (3-5). The effects of poor nutrition are most damaging in the developing larvae of honey bees, who mature into workers unable to meet the needs of their colony (6-8). It is therefore essential that we better understand the nutritional landscape experienced by honey bee larvae. In this study, we characterize the metabolic capabilities of a honey bee larvae-associated bacterium, Bombella apis (formerly Parasaccharibacter apium), and its effects on the nutritional resilience of larvae. We found that B. apis is the only bacterium associated with larvae that can withstand the antimicrobial larval diet. Further, we found that B. apis can synthesize all essential amino acids and significantly alters the amino acid content of synthetic larval diet, largely by increasing the essential amino acid lysine. Analyses of gene gain/loss across the phylogeny suggest that two distinct cationic amino acid transporters were gained by B. apis ancestors, and the transporter LysE is conserved across all sequenced strains of B. apis. This result suggests that amino acid export is a key feature conserved within the Bombella clade. Finally, we tested the impact of B. apis on developing honey bee larvae subjected to nutritional stress and found that larvae supplemented with B. apis are bolstered against mass reduction despite limited nutrition. Together, these data suggest an important role of B. apis as a nutritional mutualist of honey bee larvae.

microbiology↗

bioRxiv2020

miR-125-chinmo pathway regulates dietary restriction dependent enhancement of lifespan in Drosophila

Dietary restriction (DR) extends healthy lifespan in diverse species. Age and nutrient-related changes in the abundance of microRNAs (miRNAs) and their processing factors have been linked to organismal longevity. However, the mechanisms by which they modulate lifespan and the tissue-specific role of miRNA mediated networks in DR dependent enhancement of lifespan remains largely unexplored. We show that two neuronally enriched and highly conserved microRNAs, miR-125 and let-7 mediate the DR response in Drosophila melanogaster. Functional characterization of miR-125 demonstrates its role in neurons while its target chinmo acts both in neurons and the fat body to modulate fat metabolism and longevity. Proteomic analysis revealed that Chinmo exerts its DR effects by regulating expression of FATP, CG2017, CG9577, CG17554, CG5009, CG8778, CG9527 and FASN1. Our findings identify miR-125 as a conserved effector of DR pathway and open up the avenue for this small RNA molecule and its downstream effectors to be considered as potential drug candidates for treatment of late-onset diseases and biomarkers for healthy aging in humans.

molecular biology↗

bioRxiv2020

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

The oncometabolite L-2-hydroxyglutarate (L-2HG) is considered an abnormal product of central carbon metabolism that is capable of disrupting chromatin architecture, mitochondrial metabolism, and cellular differentiation. Under most circumstances, mammalian tissues readily dispose of this compound, as aberrant L-2HG accumulation induces neurometabolic disorders and promotes renal cell carcinomas. Intriguingly, Drosophila melanogaster larvae were recently found to accumulate high L-2HG levels under normal growth conditions, raising the possibility that L-2HG plays a unique role in insect metabolism. Here we explore this hypothesis by analyzing L-2HG levels in 18 insect species. While L-2HG was present at low-to-moderate levels in most of these species (<100 pmol/mg; comparable to mouse liver), Dipteran larvae exhibited a tendency to accumulate high L-2HG concentrations (>100 pmol/mg), with the mosquito Aedes aegypti, the blow fly Phormia regina, and three representative Drosophila species harboring concentrations that exceed 1 nmol/mg - levels comparable to those measured in mutant mice that are unable to degrade L-2HG. Overall, our findings suggest that one of the largest groups of animals on earth commonly generate high concentrations of an oncometabolite during juvenile growth, hint at a role for L-2HG in the evolution of Dipteran development, and raise the possibility that L-2HG metabolism could be targeted to restrict the growth of key disease vectors and agricultural pests.

developmental biology↗