Theranostics 2023; 13(2):438-457. doi:10.7150/thno.75973 This issue Cite

Research Paper

Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression

Sehyun Oh1, Sihyang Jo1, Martina Bajzikova2, Han Sun Kim1, Thien T. P. Dao1, Jakub Rohlena3, Jin-Mo Kim1, Jiri Neuzil2,4,5✉, Sunghyouk Park1✉

1. College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea.
2. School of Pharmacy and Medical Science, Griffith University, Southport, Qld, Australia.
3. Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
4. Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic.
5. Faculty of Science, Charles University, Prague, Czech Republic.

Citation:
Oh S, Jo S, Bajzikova M, Kim HS, Dao TTP, Rohlena J, Kim JM, Neuzil J, Park S. Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. Theranostics 2023; 13(2):438-457. doi:10.7150/thno.75973. https://www.thno.org/v13p0438.htm
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Abstract

Graphic abstract

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth.

Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation.

Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

Keywords: cancer, mitochondria, GPD2, DHAP, ether lipids


Citation styles

APA
Oh, S., Jo, S., Bajzikova, M., Kim, H.S., Dao, T.T.P., Rohlena, J., Kim, J.M., Neuzil, J., Park, S. (2023). Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. Theranostics, 13(2), 438-457. https://doi.org/10.7150/thno.75973.

ACS
Oh, S.; Jo, S.; Bajzikova, M.; Kim, H.S.; Dao, T.T.P.; Rohlena, J.; Kim, J.M.; Neuzil, J.; Park, S. Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. Theranostics 2023, 13 (2), 438-457. DOI: 10.7150/thno.75973.

NLM
Oh S, Jo S, Bajzikova M, Kim HS, Dao TTP, Rohlena J, Kim JM, Neuzil J, Park S. Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. Theranostics 2023; 13(2):438-457. doi:10.7150/thno.75973. https://www.thno.org/v13p0438.htm

CSE
Oh S, Jo S, Bajzikova M, Kim HS, Dao TTP, Rohlena J, Kim JM, Neuzil J, Park S. 2023. Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression. Theranostics. 13(2):438-457.

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