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.
|Number of pages||15|
|Journal||Cell Death and Differentiation|
|State||Published - Oct 2022|
Bibliographical noteFunding Information:
This work was supported by R01CA133429 (TG), R01CA208343 (TG), F31CA260840 (SH), R35NS116824 (MSG), R01AG066653 (RCS), and a pilot grant from P20GM121327 (University of Kentucky Center for Cancer and Metabolism). ATS is supported by National Science Foundation Graduate Research Fellowship Award (#1839289). The studies were conducted with support provided by the Redox Metabolism, Biospecimen Procurement and Translational Pathology, Flow Cytometry and Immune Monitoring, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558) at the University of Kentucky.
We thank Dr. Hiromi Sesaki at Johns Hopkins University for kindly providing the Su9-mCherry-GFP expression plasmid and Dr. Yekaterina Zaytseva for sharing the PT130 cell line. The diagram shown in Fig. 7k was created with BioRender.com.
© 2022, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology