| Summary: | Excess dietary carbohydrates are linked to dysregulation of metabolic pathways converging to mitochondria and metabolic inflexibility. Here, we determined the role of the mitochondrial pyruvate carrier (MPC) in the occurrence of this metabolic inflexibility in wild-type (WT) and MPC1-deficient (MPC1<sup>def</sup>) flies that were exposed to diets with different sucrose concentrations for 15–25 days (Standard Diet: SD, Medium-Sucrose Diet: MSD, and High-Sucrose Diet: HSD). Our results showed that MPC1<sup>def</sup> flies had lower mitochondrial respiration rates than WT flies on the SD and MSD. However, when exposed to the HSD, WT flies displayed decreased mitochondrial respiration rates compared to MPC1<sup>def</sup> flies. WT flies exposed to the HSD also displayed increased proline contribution and slightly decreased <i>MPC1</i> expression. Surprisingly, when fed the MSD and the HSD, few metabolites were altered in WT flies whereas MPC1<sup>def</sup> flies display significant accumulation of glycogen, glucose, fructose, lactate, and glycerol. Overall, this suggests that metabolic inflexibility starts to occur in WT flies after 15–25 days of exposure to the HSD whereas the MPC1<sup>def</sup> flies display metabolic inflexibility independently of the diet provided. This study thus highlights the involvement of MPC as an essential protein in Drosophila to maintain proper metabolic homeostasis during changes in dietary resources.
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