Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene‐induced senescent cells
Open accessAbstract
Metabolism is closely linked with cellular state and biological processes, but the mechanisms controlling metabolic properties in different contexts remain unclear. Cellular senescence is an irreversible growth arrest induced by various stresses, which exhibits active secretory and metabolic phenotypes. Here, we show that retinoblastoma protein (RB) plays a critical role in promoting the metabolic flow by activating both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) in cells that have undergone oncogene-induced senescence (OIS). A combination of real-time metabolic monitoring, and metabolome and gene expression analyses showed that OIS-induced fibroblasts developed an accelerated metabolic flow. The loss of RB downregulated a series of glycolytic genes and simultaneously reduced metabolites produced from the glycolytic pathway, indicating that RB upregulates glycolytic genes in OIS cells. Importantly, both mitochondrial OXPHOS and glycolytic activities were abolished in RB-depleted or downstream glycolytic enzyme-depleted OIS cells, suggesting that RB-mediated glycolytic activation induces a metabolic flux into the OXPHOS pathway. Collectively, our findings reveal that RB essentially functions in metabolic remodeling and the maintenance of the active energy production in OIS cells.
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Rb increases the flux of pyruvate through the TCA cycle and subsequently oxidative phosphorylation.
“In this way, Rb increases the flux of pyruvate through the TCA cycle and, subsequently, oxidative phosphorylation 59 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [59]
The Results (Metabolome profiling; page not provided) show that RB depletion attenuated increases in TCA-cycle metabolites in oncogene-induced senescent cells, and the Discussion says RB supports mitochondrial oxidative phosphorylation. But the Discussion only suggests that RB regulates the PDP2–PDH pathway; it does not establish that RB increases pyruvate flux through the TCA cycle. The claim states that proposed mechanism as a finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn fully senescent cells, RB stimulates mitochondrial oxidative phosphorylation.
“In fully senescent cells, RB also stimulates mitochondrial oxidative phosphorylation [227].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [227]
p53 restricts glycolysis activity of senescent cells through several mechanisms, while RB upregulates glycolytic genes, resulting in high glycolytic activity.
“In addition to stopping senescent cell proliferation, p53 and RB mediate senescence-related metabolic changes by balancing their effects on glycolysis: p53 restricts the glycolysis activity of senescent cells through several mechanisms [226], while RB upregulates glycolytic genes, resulting in high glycolytic activity [227].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [227]
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- Authors
- Takebayashi, S., Tanaka, H., Hino, S., Nakatsu, Y., Igata, T., Sakamoto, A., Narita, M., & Nakao, M.
- Affiliations
- Institute of Molecular Embryology and Genetics, Kumamoto University (JP)
- University of Cambridge (GB)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Nakao, Mitsuyoshi
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2015-05-25
- Volume
- 14
- Issue
- 4
- Pages
- 689-697
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC4531082
- OpenAlex
- W1546551973
- Cited by
- 84
- References
- 47
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 10 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 11 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 1
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Aging Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Japanese Biochemical Society/The Molecular Biology Society of Japan
- Funders
- Cancer Research UK (15890)
- Japan Society for the Promotion of Science (15H04707, 26870443, 25430178, 15K15068)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- retinoblastoma protein, oncogene-induced senescence, cellular senescence, oxidative phosphorylation, glycolysis, metabolic remodeling, mitochondrial metabolism, senescence-associated secretory phenotype, energy metabolism
- MeSH terms
- Citric Acid Cycle, Epithelial Cells, Glycolysis, Humans, Mitochondria, Oxidative Phosphorylation, Genes, ras, Signal Transduction, Gene Expression Regulation, Neoplastic, Retinoblastoma Protein, Cellular Senescence, Respiratory Mucosa, Gene Expression Profiling, Cell Line, Tumor
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