Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer

Xiaopeng Xiong; Sumati Hasani; Lyndsay E.A. Young; Dylan R. Rivas; Ashley T. Skaggs; Rebecca Martinez; Chi Wang; Heidi L. Weiss; Matthew S. Gentry; Ramon C. Sun; Tianyan Gao

doi:10.1038/s41418-022-00974-5

Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer

Xiaopeng Xiong, Sumati Hasani, Lyndsay E.A. Young, Dylan R. Rivas, Ashley T. Skaggs, Rebecca Martinez, Chi Wang, Heidi L. Weiss, Matthew S. Gentry, Ramon C. Sun, Tianyan Gao

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1913-1927
Number of pages	15
Journal	Cell Death and Differentiation
Volume	29
Issue number	10
DOIs	https://doi.org/10.1038/s41418-022-00974-5
State	Published - Oct 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Funding

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.

Funders	Funder number
NIH-funded University of Kentucky Center for Cancer and Metabolism
National Science Foundation (NSF)	1839289
National Institute of General Medical Sciences	P20GM121327
The Johns Hopkins University	PT130

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer",

abstract = "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.",

author = "Xiaopeng Xiong and Sumati Hasani and Young, {Lyndsay E.A.} and Rivas, {Dylan R.} and Skaggs, {Ashley T.} and Rebecca Martinez and Chi Wang and Weiss, {Heidi L.} and Gentry, {Matthew S.} and Sun, {Ramon C.} and Tianyan Gao",

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AU - Rivas, Dylan R.

AU - Skaggs, Ashley T.

AU - Martinez, Rebecca

AU - Wang, Chi

AU - Weiss, Heidi L.

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AU - Sun, Ramon C.

AU - Gao, Tianyan

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AB - 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.

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Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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