Carnitine Palmitoyltransferase 1A Promotes Mitochondrial Fission by Enhancing MFF Succinylation in Ovarian Cancer

Overview

Journal Commun Biol

Specialty Biology

Date 2023 Jun 8

PMID 37291333

Authors

Yaqin Zhu

Yue Wang

Ying Li

Zhongqi Li

Wenhui Kong

Xiaoxuan Zhao

Shuting Chen

Liting Yan

Lenan Wang

Yunli Tong

Huanjie Shao

Affiliations

Soon will be listed here.

Abstract

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

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References

Sheng J, Li H, Dai Q, Lu C, Xu M, Zhang J . NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy. Cell Physiol Biochem. 2018; 48(4):1675-1693. DOI: 10.1159/000492292. View

Prip-Buus C, Thuillier L, Abadi N, Prasad C, Dilling L, Klasing J . Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community. Mol Genet Metab. 2001; 73(1):46-54. DOI: 10.1006/mgme.2001.3176. View

Li X, Wu Q, Ma F, Zhang X, Cai L, Yang X . Mitochondrial fission factor promotes cisplatin resistancein hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai). 2022; 54(3):301-310. PMC: 9828151. DOI: 10.3724/abbs.2022007. View

Yan X, Li P, Zhan Y, Qi M, Liu J, An Z . Dihydroartemisinin suppresses STAT3 signaling and Mcl-1 and Survivin expression to potentiate ABT-263-induced apoptosis in Non-small Cell Lung Cancer cells harboring EGFR or RAS mutation. Biochem Pharmacol. 2018; 150:72-85. DOI: 10.1016/j.bcp.2018.01.031. View

Liu G, Luo Q, Li H, Liu Q, Ju Y, Song G . Increased Oxidative Phosphorylation Is Required for Stemness Maintenance in Liver Cancer Stem Cells from Hepatocellular Carcinoma Cell Line HCCLM3 Cells. Int J Mol Sci. 2020; 21(15). PMC: 7432880. DOI: 10.3390/ijms21155276. View

Pacilli A, Calienni M, Margarucci S, dApolito M, Petillo O, Rocchi L . Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis. J Natl Cancer Inst. 2013; 105(7):489-98. DOI: 10.1093/jnci/djt030. View

Berman S, Pineda F, Hardwick J . Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ. 2008; 15(7):1147-52. PMC: 2614113. DOI: 10.1038/cdd.2008.57. View

Cherok E, Xu S, Li S, Das S, Meltzer W, Zalzman M . Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5-dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics. Mol Biol Cell. 2016; 28(3):396-410. PMC: 5341724. DOI: 10.1091/mbc.E16-04-0208. View

Xiong X, Hasani S, Young L, Rivas D, Skaggs A, Martinez R . Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer. Cell Death Differ. 2022; 29(10):1913-1927. PMC: 9525627. DOI: 10.1038/s41418-022-00974-5. View

10.

Xie Z, Jones A, Deeney J, Hur S, Bankaitis V . Inborn Errors of Long-Chain Fatty Acid β-Oxidation Link Neural Stem Cell Self-Renewal to Autism. Cell Rep. 2016; 14(5):991-999. PMC: 4749429. DOI: 10.1016/j.celrep.2016.01.004. View

11.

Liu A, Kage F, Higgs H . Mff oligomerization is required for Drp1 activation and synergy with actin filaments during mitochondrial division. Mol Biol Cell. 2021; 32(20):ar5. PMC: 8684745. DOI: 10.1091/mbc.E21-04-0224. View

12.

Archer S . Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. N Engl J Med. 2013; 369(23):2236-51. DOI: 10.1056/NEJMra1215233. View

13.

Qi M, Dai D, Liu J, Li Z, Liang P, Wang Y . AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics. Oncogene. 2020; 39(13):2707-2723. DOI: 10.1038/s41388-020-1176-9. View

14.

Li R, Li X, Zhao J, Meng F, Yao C, Bao E . Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. Theranostics. 2022; 12(2):976-998. PMC: 8692896. DOI: 10.7150/thno.63751. View

15.

Yeo W, Chan S, Mo F, Chu C, Hui J, Tong J . Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response. BMC Cancer. 2015; 15:395. PMC: 4434865. DOI: 10.1186/s12885-015-1334-6. View

16.

Nieman K, Kenny H, Penicka C, Ladanyi A, Buell-Gutbrod R, Zillhardt M . Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011; 17(11):1498-503. PMC: 4157349. DOI: 10.1038/nm.2492. View

17.

Knobloch M, Pilz G, Ghesquiere B, Kovacs W, Wegleiter T, Moore D . A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity. Cell Rep. 2017; 20(9):2144-2155. PMC: 5583518. DOI: 10.1016/j.celrep.2017.08.029. View

18.

Quintana-Cabrera R, Manjarres-Raza I, Vicente-Gutierrez C, Corrado M, Bolanos J, Scorrano L . Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria. Redox Biol. 2021; 41:101944. PMC: 8039725. DOI: 10.1016/j.redox.2021.101944. View

19.

Sanchez-Alvarez R, De Francesco E, Fiorillo M, Sotgia F, Lisanti M . Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity. Front Oncol. 2020; 10:1776. PMC: 7642822. DOI: 10.3389/fonc.2020.01776. View

20.

Wen Y, Xing X, Harris J, Zaytseva Y, Mitov M, Napier D . Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis. 2017; 8(2):e2593. PMC: 5386470. DOI: 10.1038/cddis.2017.21. View