Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.

Autor:	Oh S; College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea., Jo S; College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea., Bajzikova M; School of Pharmacy and Medical Science, Griffith University, Southport, Qld, Australia., Kim HS; College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea., Dao TTP; College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea., Rohlena J; Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic., Kim JM; College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea., Neuzil J; School of Pharmacy and Medical Science, Griffith University, Southport, Qld, Australia.; Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic.; Faculty of Science, Charles University, Prague, Czech Republic., Park S; College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea.
Jazyk:	angličtina
Zdroj:	Theranostics [Theranostics] 2023 Jan 01; Vol. 13 (2), pp. 438-457. Date of Electronic Publication: 2023 Jan 01 (Print Publication: 2023).
DOI:	10.7150/thno.75973
Abstrakt:	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. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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