Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Molecular and Cellular Biochemistry

First Advisor

Dr. Tianyan Gao


Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Consequently, metabolic reprogramming has been increasingly recognized as a major mechanism that fuels tumorigenesis and disease progression. Here, we have investigated the role of a pro-fission factor, Dynamin-Related Protein 1 (Drp1), in promoting metabolic adaptation in colon cancer.

Our studies have shown that fatty acid (FAs) uptake alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation through the activation of Drp1. Uptake of FAs induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site, leading to enhanced Drp1 dimerization and interaction with Mitochondrial Fission Factor (MFF). Consequently, knockdown of Drp1 or MFF attenuates FA-induced mitochondrial fission. Moreover, results from the metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks FA-induced metabolic reprograming by inhibiting FA utilization. Functionally, Drp1 knockdown 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.

While investigating the role of Drp1 in regulating glucose metabolism in colon cancer, we show that silencing Drp1 induces glycogen accumulation to support cell survival. Drp1 knockdown decreases mitochondrial respiration, which results in increased glucose uptake. However, increased availability of glucose leads to glycogen accumulation rather than enhanced glycolysis in colon cancer cells. Consistently, results from GC/MS analysis of cellular metabolites show that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated in Drp1 knockdown cells whereas pyruvate and other TCA cycle metabolites remain unchanged. Mechanistically, Drp1 depletion activates AMP-activated protein kinase (AMPK) to promote the expression of glycogen synthase 1 (GYS1). Silencing GYS1 abolishes glycogen accumulation in Drp1 knockdown cells. Using Apc-derived 3D organoid model, we demonstrate that the glycogen levels are elevated in tumor organoids upon deletion of Drp1. Similarly, increased GYS1 expression and glycogen levels are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Furthermore, increased glycogen storage allows Drp1 knockdown cells to survive glucose starvation conditions. Co-targeting glycogen phosphorylase-mediated glycogenolysis enhances the chemosensitivity of colon cancer cells to irinotecan treatment. Collectively, these results suggest that Drp1 inhibition by itself is unlikely to be sufficient to eradicate cancer cells as adaptive metabolic mechanisms are activated to sustain cell survival. However, combined inhibition of compensative metabolic pathways may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.

Taken together, our study identifies Drp1 as a key mediator that connects cellular metabolism with cancer cell signaling. By providing novel insights into the role of mitochondrial dynamics in controlling metabolic adaptations, our findings will help guide the future development of mitochondrial targeted therapies in colon cancer.

Digital Object Identifier (DOI)

Funding Information

This study was supported by the NCI Ruth L. Kirschstein Predoctoral NRSA F31 Fellowship (1F31CA260840-01) from 2021-2023.

Available for download on Thursday, July 31, 2025