{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T01:15:07Z","timestamp":1768612507421,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Narayana Nethralaya Foundation, Bangalore, India"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mutations in the RB1 locus leading to a loss of functional Rb protein cause intraocular tumors, which uniquely affect children worldwide. These tumors demonstrate rapid proliferation, which has recently been shown to be associated with an altered metabolic signature. We found that retinoblastoma tumors and in-vitro models lack Hexokinase 1 (HK1) and exhibit elevated fatty acid oxidation. We show that ectopic expression of RB1 induces HK1 protein in Rb null cells, and both RB1 and HK1 can mediate a metabolic switch from OXPHOS to glycolysis with increased pyruvate levels, reduced ATP production and reduced mitochondrial mass. Further, cells lacking Rb or HK1 can flexibly utilize glutamine and fatty acids to enhance oxidative phosphorylation-dependent ATP generation, as revealed by metabolic and biochemical assays. Thus, loss of Rb and HK1 in retinoblastoma reprograms tumor metabolic circuits to enhance the glucose-independent TCA (tricarboxylic acid) cycle and the intermediate NAD+\/NADH ratios, with a subsequent increase in fatty-acid derived L-carnitine to enhance mitochondrial OXPHOS for ATP production instead of glycolysis dependence. We also demonstrate that modulation of the Rb-regulated transcription factor E2F2 does not result in any of these metabolic perturbations. In conclusion, we demonstrate RB1 or HK1 as critical regulators of the cellular bioenergetic profile and identify the altered tumor metabolism as a potential therapeutic target for cancers lacking functional Rb protein.<\/jats:p>","DOI":"10.3390\/cells11203182","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:50:01Z","timestamp":1665449401000},"page":"3182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Lack of Retinoblastoma Protein Shifts Tumor Metabolism from Glycolysis to OXPHOS and Allows the Use of Alternate Fuels"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8104-8652","authenticated-orcid":false,"given":"Vishnu","family":"Suresh Babu","sequence":"first","affiliation":[{"name":"GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore 560099, India"},{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gagan","family":"Dudeja","sequence":"additional","affiliation":[{"name":"Retinoblastoma Service, Narayana Nethralaya, Bangalore 560099, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"SA","sequence":"additional","affiliation":[{"name":"Agilent Technologies India Pvt Ltd., Bangalore 560048, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anadi","family":"Bisht","sequence":"additional","affiliation":[{"name":"GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore 560099, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohit","family":"Shetty","sequence":"additional","affiliation":[{"name":"GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore 560099, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephane","family":"Heymans","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Bus 911, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-3107","authenticated-orcid":false,"given":"Nilanjan","family":"Guha","sequence":"additional","affiliation":[{"name":"Agilent Technologies India Pvt Ltd., Bangalore 560048, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6570-5891","authenticated-orcid":false,"given":"Arkasubhra","family":"Ghosh","sequence":"additional","affiliation":[{"name":"GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore 560099, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/323643a0","article-title":"A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma","volume":"323","author":"Friend","year":"1986","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/ICU.0b013e328338676a","article-title":"Retinoblastoma management: Advances in enucleation, intravenous chemo reduction, and intra-arterial chemotherapy","volume":"21","author":"Shields","year":"2010","journal-title":"Curr. 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