Monitoring fatty acid trafficking during Drosophila melanogaster oogenesis reveals a role for the triglyceride synthase DGAT1 in protecting mitochondrial integrity
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Successful oogenesis requires the precise coordination of nutrient uptake, storage, and utilization to meet the high metabolic demands of egg production. In mammals, fatty acid (FA) metabolism has emerged as a key driver of oocyte maturation; however, the mechanisms by which follicles regulate FA trafficking and utilization remain poorly understood across all systems. To address these issues, we leverage the genetic tractability of Drosophila melanogaster oogenesis. We found that nurse cell mitochondria are metabolically active and catabolize FA in a stage-dependent manner, with fatty acid oxidation (FAO) peaking during mid-oogenesis. By exposing explanted follicles to fluorescently labeled FAs, we monitored FA trafficking and found massive enrichment in lipid droplets. Mutants for the triglyceride lipase ATGL exhibited a reduction in both mitochondrial membrane potential and FAO, suggesting that mitochondria utilize FA from triglycerides stored in LDs. To determine the significance of this transient FA storage in LDs, we prevented the formation of nurse cell LDs with mutations in the triglyceride synthase DGAT1. The DGAT1 mutant follicles display excess accumulation of FAs in mitochondria, mitochondrial stress, and developmental arrest. We find that this mitochondrial dysfunction and follicle arrest are consequences of FA toxicity to mitochondria: limiting FA influx into follicles or FA import into mitochondria alleviates these defects. Our findings demonstrate that LD-derived FAs are actively mobilized to fuel the energy demands of oogenesis while LDs buffer against lipotoxicity, revealing a critical balance between FA storage and oxidation. These findings highlight LDs as central hubs regulating energy homeostasis and developmental progression in the follicle.
Author Summary
Oogenesis places extraordinary metabolic demands on the follicle, yet the energy source for follicle development is not well understood. In fruit flies, follicles take in large amounts of lipids from the hemolymph, the insect blood, and accumulate massive fat stores in the form of lipid droplets. Whether these stores are reserved for the embryo or already power oogenesis was unclear. Using mutants and fluorescent probes for metabolic activity, we found that some fatty acids are released from the lipid droplets and power energy production in mitochondria; this energy source is important for successful oogenesis. We then fed flies fluorescently labeled fatty acids and determined how these fatty acids travel when lipid droplet formation can occur versus when it is abolished. In the former case, fatty acids accumulate in lipid droplets; in the latter, they flood into mitochondria, causing mitochondrial dysfunction, reduced ATP levels, and follicle death. We can correct all these defects by limiting lipid influx specifically into mitochondria. Our findings reveal an important role for lipid droplets during oogenesis. They act as a metabolic buffer, supplying sufficient amounts of fatty acids to mitochondria for energy production while shielding the mitochondria from toxic lipid levels.
