Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression

0572138 - BTÚ 2024 RIV AU eng J - Článek v odborném periodiku
Oh, S. - Jo, S. - Bajzikova, M. - Kim, H. S. - Dao, T. T. P. - Rohlena, Jakub - Kim, J. - Neužil, Jiří - Park, S.
Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.
Theranostics. Roč. 13, č. 2 (2023), s. 438-457. ISSN 1838-7640. E-ISSN 1838-7640
Grant CEP: GA ČR(CZ) GA20-05942S; GA ČR(CZ) GX21-04607X; GA ČR(CZ) GA20-18513S
Institucionální podpora: RVO:86652036
Klíčová slova: cancer * mitochondria * gpd2 * dhap * ether lipids
Obor OECD: Cell biology
Impakt faktor: 12.4, rok: 2022
Způsob publikování: Open access
https://www.thno.org/v13p0438.htm

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 (rho 0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth.Methods and results: Despite extensive metabolic downregulation, rho 0 cells exhibited high glycerol-3phosphate (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.
Trvalý link: https://hdl.handle.net/11104/0343304