Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells

Okahashi, Nobuyuki; Shima, Tomoki; Kondo, Yuya; Araki, Chie; Tsuji, Shuma; Sawai, Akane; Uehara, Hikaru; Kohno, Susumu; Shimizu, Hiroshi; Takahashi, Chiaki; Matsuda, Fumio

doi:https://doi.org/10.1016/j.ymben.2025.08.002

Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells

Okahashi, Nobuyuki; Shima, Tomoki; Kondo, Yuya et al.

Metabolic Engineering, 2025, 92, 185-193

Number of Access:8（2025-11-08 21:32 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/102861

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Title	Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells
Creator	NRID 1000030802748 1000030802748 ORCID 0000-0001-9582-355X 0000-0001-9582-355X researchmap permalink okahashinobuyuki okahashinobuyuki Scopus Author ID 56549714700 56549714700 CreatorName Okahashi, Nobuyuki
	CreatorName Shima, Tomoki
	CreatorName Kondo, Yuya
	CreatorName Araki, Chie
	CreatorName Tsuji, Shuma
	CreatorName Sawai, Akane
	CreatorName Uehara, Hikaru
	NRID 1000030625463 1000030625463 CreatorName Kohno, Susumu
	NRID 1000000226250 1000000226250 ORCID 0000-0002-8986-0861 0000-0002-8986-0861 researchmap permalink hiroshi_shimizu hiroshi_shimizu Scopus Author ID 55230249300 55230249300 CreatorName Shimizu, Hiroshi
	NRID 1000050283619 1000050283619 CreatorName Takahashi, Chiaki
	NRID 1000050462734 1000050462734 ORCID 0000-0003-1091-778X 0000-0003-1091-778X researchmap permalink fumio_matsuda fumio_matsuda Scopus Author ID 7202165617 7202165617 CreatorName Matsuda, Fumio
Subject	Aerobic glycolysis
	Caner metabolism
	Flux balance analysis
	Metabolic flux analysis
	Metabolic heat
Description	Okahashi N., Shima T., Kondo Y., et al. Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells. Metabolic Engineering 92, 185 (2025); https://doi.org/10.1016/j.ymben.2025.08.002.
Abstract	Adenosine triphosphate (ATP) regeneration by substrate-level phosphorylation is a general feature of cancer metabolism, even under normoxic conditions (aerobic glycolysis). However, it is unclear why cancer cells prefer inefficient aerobic glycolysis over the highly efficient process of oxidative phosphorylation for ATP regeneration. To investigate the metabolic principles underlying aerobic glycolysis, we performed 13C-metabolic flux analysis of 12 cultured cancer cell lines and explored the metabolic constraints required to reproduce the results using in silico metabolic simulations. We found that the measured flux distribution can be reproduced by maximizing the ATP consumption in the flux balance analysis considering a limitation of metabolic heat dissipation (enthalpy change). Consistent with the simulation, OXPHOS inhibition induced metabolic redirection to aerobic glycolysis while maintaining the intracellular temperature. Furthermore, the dependency on aerobic glycolysis was partly alleviated upon culturing at low temperatures. Our data suggest that metabolic thermogenesis is an important factor in understanding aerobic glycolysis in cancer cells and that an advantage of aerobic glycolysis is the reduction in metabolic heat generation during ATP regeneration.
Publisher	Academic Press Inc.
Source Title	Metabolic Engineering
Volume (Issue)	92
Page	185-193
Date of Issued	2025-11-01
Language	English
Handle URL	https://hdl.handle.net/11094/102861
PISSN	10967176
eISSN	10967184
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.ymben.2025.08.002
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Metabolic Engineering. 2025, 92, p. 185-193
DC.title	Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells
DC.creator	Okahashi, Nobuyuki
	Shima, Tomoki
	Kondo, Yuya
	Araki, Chie
	Tsuji, Shuma
	Sawai, Akane
	Uehara, Hikaru
	Kohno, Susumu
	Shimizu, Hiroshi
	Takahashi, Chiaki
	Matsuda, Fumio
DC.publisher	Academic Press Inc.
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-11-01
DC.identifier	https://doi.org/10.1016/j.ymben.2025.08.002
DC.subject	Aerobic glycolysis
	Caner metabolism
	Flux balance analysis
	Metabolic flux analysis
	Metabolic heat
DC.description	Okahashi N., Shima T., Kondo Y., et al. Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells. Metabolic Engineering 92, 185 (2025); https://doi.org/10.1016/j.ymben.2025.08.002.
DCTERMS.abstract	Adenosine triphosphate (ATP) regeneration by substrate-level phosphorylation is a general feature of cancer metabolism, even under normoxic conditions (aerobic glycolysis). However, it is unclear why cancer cells prefer inefficient aerobic glycolysis over the highly efficient process of oxidative phosphorylation for ATP regeneration. To investigate the metabolic principles underlying aerobic glycolysis, we performed 13C-metabolic flux analysis of 12 cultured cancer cell lines and explored the metabolic constraints required to reproduce the results using in silico metabolic simulations. We found that the measured flux distribution can be reproduced by maximizing the ATP consumption in the flux balance analysis considering a limitation of metabolic heat dissipation (enthalpy change). Consistent with the simulation, OXPHOS inhibition induced metabolic redirection to aerobic glycolysis while maintaining the intracellular temperature. Furthermore, the dependency on aerobic glycolysis was partly alleviated upon culturing at low temperatures. Our data suggest that metabolic thermogenesis is an important factor in understanding aerobic glycolysis in cancer cells and that an advantage of aerobic glycolysis is the reduction in metabolic heat generation during ATP regeneration.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	102861
citation_title	Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells
citation_author	Okahashi, Nobuyuki
	Shima, Tomoki
	Kondo, Yuya
	Araki, Chie
	Tsuji, Shuma
	Sawai, Akane
	Uehara, Hikaru
	Kohno, Susumu
	Shimizu, Hiroshi
	Takahashi, Chiaki
	Matsuda, Fumio
citation_publisher	Academic Press Inc.
citation_language	English
citation_date	2025-11-01
citation_journal_title	Metabolic Engineering
citation_volume	92
citation_firstpage	185
citation_lastpage	193
citation_doi	https://doi.org/10.1016/j.ymben.2025.08.002
citation_public_url	https://hdl.handle.net/11094/102861

Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells

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