2 deoxy-D-glucose augments the mitochondrial respiratory chain in heart

Sep 4, 2026

2-deoxy-D-glucose (2DG) has been explored for COVID-19 treatment because SARS-CoV-2 infection increases glycolysis while reducing mitochondrial function; 2DG represses glycolysis and promotes respiration, thereby limiting viral replication. However, pleiotropic effects observed in cultured cells do not clarify the in vivo outcome, particularly given reported detrimental effects on rodent heart. This work shows extended intermittent 2DG mainly augments the heart’s mitochondrial respiratory chain proteome without vacuolization, hypertrophy, or fibrosis, suggesting increased oxidative capacity and a metabolic state opposite to infected cells.

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CategoryResearch & Report

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Results

Proteomic analysis accurately reflects mitochondrial respiratory chain changes

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN 2 deoxy‑D‑glucose augments the mitochondrial respiratory chain in heart IratiAiestaran‑Zelaia1,2, María Jesús Sánchez‑Guisado2,3, Marina Villar‑Fernandez1, Mikel Azkargorta4, Lucia Fadon‑Padilla2, Uxoa Fernandez‑Pelayo1, Diego Perez‑Rodriguez5, Pedro Ramos‑Cabrer2,6, Antonella Spinazzola5, Félix Elortza4 , Jésus Ruíz‑Cabello2,3,6,7,10* & Ian J. Holt1,5,6,8,9,10* 2‑Deoxy‑D‑glucose (2DG) has recently received emergency approval for the treatment ofCOVID‑19 in India, after a successful clinical trial. SARS‑CoV‑2 infection of cultured cells is accompanied by elevated glycolysis and decreased mitochondrial function, whereas 2DG represses glycolysis and stimulates respiration, and restricts viral replication. While 2DG has pleiotropic effects on cell metabolism in cultured cells it is not known which of these manifests in vivo. On the other hand, it is known that 2DG given continuously can have severe detrimental effects on the rodent heart. Here, we showthatthe principal effect of an extended, intermittent 2DG treatment on mice is to augment the mitochondrial respiratory chain proteome in the heart; importantly, this occurs without vacuolization, hypertrophy or fibrosis. The increase in the heart respiratory chain proteome suggests an increase in mitochondrial oxidative capacity, which could compensate for the energy deficit caused by the inhibition of glycolysis. Thus, 2DG in the murine heart appears to induce a metabolic configuration that is the opposite of SARS‑CoV‑2 infected cells, which could explain the compound’s ability to restrict the propagation of the virus to the benefit of patients with COVID‑19 disease. 2 deoxy-D-glucose (2DG) reconfigures cell metabolism by restricting glucose consumption in cells and tissues owing to inhibition of glycolysis1; as such, there is considerable interest in its potential as an anti-cancer agent, given the highly glycolytic nature of many cancer cells2. Recently, 2DG has attracted further interest as it restricts SARS-CoV-2 viral replication in infected human cultured cells3, and it has recently received emergency approval for the treatment of COVID-19 in India, after a successful clinical trial4. Following infection, viruses usurp control of the host cell and remodel processes and pathways to optimize viral production. Hence, configuring cell metabolism opposite to the preferences of the virus represents a potentially powerful anti-viral strategy. Previous studies have shown that glycolysis is upregulated in response to viral infection, and that 2DG restricts the replication of viruses as diverse as HSV, Rhinovirus, Norovirus and SARSCoV-23,5,6. However, inhibition of glycolysis is merely the most prominent of a number of pleiotropic effects of 2DG on cell metabolism. Deciphering 2DG’s effects in vivo is important to understand how it might restrict viral infections, such as SARS-CoV-2, and any complications that might segue, especially those affecting the heart where 2DG has been reported to have serious detrimental effects in rodents7. Several intersecting cellular pathways and processes are linked to SARS-CoV-2 replication and propagation, including TORC1, HIF1α and one-carbon metabolism8–10, although the importance of each of these is still the 1Biodonostia Health Research Institute, 20014 San Sebastián, Spain. 2Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 182, 20014 San Sebastián, Spain. 3Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain. 4Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, 48160 Derio, Spain. 5Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London NW3 2PF, UK. 6IKERBASQUE, Basque Foun

FAQs

What main in vivo effect does extended intermittent 2DG have on the mouse heart?

It augments the mitochondrial respiratory chain proteome in the heart without vacuolization, hypertrophy, or fibrosis.

How does 2DG relate to the metabolic changes caused by SARS-CoV-2 infection?

SARS-CoV-2 infection of cultured cells elevates glycolysis and decreases mitochondrial function, while 2DG represses glycolysis and stimulates respiration, restricting viral replication.

Why might increased mitochondrial oxidative capacity matter for COVID-19?

The increased respiratory chain proteome suggests higher mitochondrial oxidative capacity, which could compensate for the energy deficit caused by glycolysis inhibition and oppose the infected-cell metabolic configuration.

Sep 4, 2026

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