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Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apc f/f /Villin-Cre ERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment., (© 2023. The Author(s).)

Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)