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Cited by 190Cancer, Hypoxia, and MetabolismMitochondrial Function and PathologyMetabolism, Diabetes, and Cancer

ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect

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Maldonado, Eduardo N., Lemasters, John J.·2014·Mitochondrion
DOI 10.1016/j.mito.2014.09.002PMC PMC4254332
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Abstract

Non-proliferating cells generate the bulk of cellular ATP by fully oxidizing respiratory substrates in mitochondria. Respiratory substrates cross the mitochondrial outer membrane through only one channel, the voltage dependent anion channel (VDAC). Once in the matrix, respiratory substrates are oxidized in the tricarboxylic acid cycle to generate mostly NADH that is further oxidized in the respiratory chain to generate a proton motive force comprised mainly of membrane potential (ΔΨ) to synthesize ATP. Mitochondrial ΔΨ then drives the release of ATP(4-) from the matrix in exchange for ADP(3-) in the cytosol via the adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane. Thus, mitochondrial function in non-proliferating cells drives a high cytosolic ATP/ADP ratio, essential to inhibit glycolysis. By contrast, the bioenergetics of the Warburg phenotype of proliferating cells is characterized by enhanced aerobic glycolysis and the suppression of mitochondrial metabolism. Suppressed mitochondrial function leads to lower production of mitochondrial ATP and hence lower cytosolic ATP/ADP ratios that favor enhanced glycolysis. Thus, the cytosolic ATP/ADP ratio is a key feature that determines if cell metabolism is predominantly oxidative or glycolytic. Here, we describe two novel mechanisms to explain the suppression of mitochondrial metabolism in cancer cells: the relative closure of VDAC by free tubulin and the inactivation of ANT. Both mechanisms contribute to low ATP/ADP ratios that activate glycolysis.

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  • Itraconazole directly binds to and blocks mitochondrial Voltage-Dependent Anion Channel 1 (VDAC1), causing a decrease in cellular energy levels that activates AMPK.

    “A decrease in cellular energy levels was demonstrated to be the consequence of ITZ direct binding to and blockage of the mitochondrial Voltage-Dependent Anion Channel 1 (VDAC1), a crucial regulator of mitochondrial metabolism, which activates AMPK.25”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [25]

    The Introduction sections on VDAC and mitochondrial metabolism report that VDAC conductance regulates mitochondrial ATP delivery and that inhibiting VDAC can lower the ATP/ADP ratio. They do not say that itraconazole binds or blocks VDAC1, or that this mechanism activates AMPK (searched: itraconazole, ITZ, AMPK). (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • VDAC1 is a unique target for endothelial cell AMPK/mTOR pathway regulation.

    “Consequently, it was demonstrated that VDAC1 is a unique target for endothelial cell AMPK/mTOR pathway regulation.”

    From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [25]

    The Introduction sections on VDAC and mitochondrial metabolism discuss VDAC isoforms in tumor cells, including VDAC1, but do not address endothelial cells or AMPK/mTOR pathway regulation. Searches for “endothelial,” “AMPK,” and the claimed pathway found no passage establishing VDAC1 as a unique target in that setting. The indexed passages provide no page numbers. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • The EnKF cannot narrow the UDP-Glc band, since UDP-Glc is unobservable and its synthesis is modelled as a fixed function of extracellular glucose that neglects transport and the regulation of glycolytic flux.

    “The EnKF cannot narrow this band, since UDP-Glc is unobservable and its synthesis is modelled as a fixed function of extracellular glucose that neglects transport and the regulation of glycolytic flux [52].”

    From Soft sensing of intracellular states for CHO cell bioprocessing with Ensemble Kalman Filters (2026) · cites this paper as [52]

    The Introduction discusses glucose metabolism and the Conclusion discusses regulation of glycolysis by ATP/ADP ratios, but neither addresses the claimed UDP-Glc model. Searches for EnKF, UDP-Glc observability, and UDP-glucose synthesis found no passage supporting the asserted reason the band cannot narrow. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Authors
Maldonado, E. N., & Lemasters, J. J.
Affiliations
  • Medical University of South Carolina (US)
  • Russian Academy of Sciences (RU)
Corresponding author
Lemasters, John J.
ORCID
Venue
Mitochondrion
Publisher
Elsevier BV
Published
2014-11
Volume
19
Pages
78-84
ISSN
1567-7249 (ISSN-L)
DOI
10.1016/j.mito.2014.09.002
PMC
PMC4254332
OpenAlex
W2018209127
Cited by
190
References
80
Citations by year
2026: 20 · 2025: 16 · 2024: 15 · 2023: 18 · 2022: 11 · 2021: 23 · 2020: 18 · 2019: 13 · 2018: 15 · 2017: 17 · 2016: 12 · 2015: 11 · 2014: 1
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Mitochondrion (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • American Cancer Society (13-043-01-IRG)
  • University of South Carolina (AA022815, CA138313, DK037034, DK073336)
  • Ministry of Education and Science of the Russian Federation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
ATP/ADP ratio, Warburg effect, aerobic glycolysis, mitochondrial metabolism, voltage-dependent anion channel, adenine nucleotide translocase, mitochondrial membrane potential, glycolysis regulation, mitochondrial outer membrane
MeSH terms
Adenosine Diphosphate, Adenosine Triphosphate, Animals, Energy Metabolism, Mitochondria, Neoplasms, Oxygen Consumption

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