Biology subjects

Shefali, S. A.

Publications and source records attributed to Shefali, S. A..

3 recordsLinked to original sources

bioRxiv2026

Drosophila melanogaster lactate dehydrogenase deficiency recapitulates the exercise intolerance of human glycogen storage disease type XI

Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme that commonly exhibits altered expression in human diseases such as cancers and neurodegeneration, making it a valuable disease biomarker and putative therapeutic target. However, any treatment targeting LDHA will also disrupt normal metabolism, underscoring the need to investigate physiological consequences of inhibiting this enzyme. We previously established the fruit fly Drosophila melanogaster as a genetic model for studying LDH function in the context of growth, metabolism, and development. Here we expand upon those studies by investigating a serendipitous observation that Ldh mutant larvae exhibit diet-dependent lethality. Using a multiomic approach, we discovered this diet-dependent phenotype is independent of nutritional composition. Instead, Ldh mutant larvae are exercise intolerant and display reduced mobility, rendering mutant larvae sensitive to food consistency. Moreover, tissue-specific analysis reveals that LDH activity within muscle and peripheral glia are essential for larval viability raised on solid food. Intriguingly, these phenotypes mirror the pathophysiology of LDHA deficiency (Glycogen Storage Disease Type XI; GSD Type XI) in humans, where mild symptoms are exacerbated by physical exertion and environmental stress. Together, our findings further highlight the value of using Drosophila to explore the developmental and physiological consequences of Ldh inhibition. SUMMARY STATEMENTLoss of lactate dehydrogenase in Drosophila causes exercise intolerance and diet-dependent lethality, revealing conditional phenotypes that mirror those associated with human LDH-A deficiency.

developmental biology↗

bioRxiv2025

New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster

D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 (IDH1) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from -ketoglutarate (KG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo, we generated two novel loss-of-function mutations in the Drosophila melanogaster gene D2hgdh and validated that these alleles result in ectopic D-2HG. Moreover, we observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, our efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology.

genetics↗

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↗