Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells

Wang, Yahui; Stancliffe, Ethan; Fowle-Grider, Ronald; Wang, Rencheng; Wang, Cheng; Schwaiger-Haber, Michaela; Shriver, Leah P.; Patti, Gary J.

doi:10.1016/j.molcel.2022.07.007

Cited by 94 publications

(104 citation statements)

References 57 publications

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“…Hence, UCP2 shifts the glycolysis-dependent metabolism to oxidative phosphorylation, which significantly decreases the proliferation of B16F10 cells and thus reduces the cells’ tumorigenic capacity. These results are consistent with a recently published study indicating that saturation of the mitochondrial malate shuttle, which uses a nicotinamide adenine dinucleotide (NADH) cofactor to reduce oxaloacetate to malate, redirects proliferative cellular metabolism to aerobic glycolysis [ 133 ]. To go further, metabolomics fluxes using C 13 -labeled glucose caused an 18% reduction in glucose consumption by the UCP2-overexpressing JB6 P+ murine skin epidermal cell line [ 134 ].…”

Section: Ucp2 and Cancersupporting

confidence: 93%

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

Luby

Alves-Guerra

2022

IJMS

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Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.

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Section: Ucp2 and Cancersupporting

confidence: 93%

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

Luby

Alves-Guerra

2022

IJMS

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“…S2E, F). Overall, we were able to confirm PEPCK2 as the culprit for the 13 C enrichment into serine from glutamine (Fig. 3F).…”

Section: Glutamine Metabolism Is Redirected Towards Ssp Under Glycoly...mentioning

confidence: 58%

PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle

Benzarti

Oudin

Viry

et al. 2023

Preprint

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Throughout the metastatic cascade, cancer cells are faced with harsh metabolic environments and nutritional stresses which apply selection pressure leaving only the most metabolically resilient cells to survive and form metastases. Metabolic characterisation of such cell populations in vitro is currently challenging. Using galactose as a tool compound to mimic glycolytic limitation within the tumour microenvironment of primary and secondary neoplastic sites, we were able to uncover metabolic flexibility and plasticity of cancer cells in vitro. In contrast to the established idea that high glycolytic flux and expression of PKM2 redirects carbons towards anabolic routes such as the pentose phosphate pathway and serine synthesis pathway (SSP), we have discovered by using stable-isotope tracing that also glycolytic limitation results in metabolic rewiring. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near complete block of pyruvate kinase isozyme M2 (PKM2) to divert carbons towards SSP. Simultaneously, TCA cycle flux is sustained and oxygen consumption is increased, both supported by glutamine. Glutamine not only supports TCA cycle flux but also SSP via distinct mechanisms. Due to PKM2 block, malic enzyme exclusively supports TCA cycle flux while mitochondrial phosphoenolpyruvate carboxykinase supports SSP. Moreover, by using genetic modifications of different one-carbon (1C) cycle enzymes, we are able to reverse the PKM2 block suggesting a link between mitochondrial 1C cycle and pyruvate kinase. Thus we show that PKM2 inhibition acts as a branching point to direct glycolytic and glutamine carbons into distinct routes, overall supporting the metabolic plasticity and flexibility of cancer cells.

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“…These results suggest that I3C affects the expression of glycolysis-related proteins, not at the RNA level, and these changes negatively correlate with MMP. To study how I3C regulates the expression of glycolysis-related genes at the post-transcriptional level, in the following experiments we focused on LDHA because it plays a key role in the regeneration of nicotinamide adenine dinucleotide (NAD+), which is required to maintain glycolysis [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells

Zhang

et al. 2022

Pharmaceuticals

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Certain cancer cells prefer aerobic glycolysis rather than oxidative phosphorylation for energy supply. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and regains NAD+ so that glycolysis is continued. As a pivotal enzyme to promote smooth glycolysis, LDHA plays an important role in carcinogenesis. Indole-3-carbinol (I3C) has displayed antitumor activity, but the exact mechanism remains to be identified. In this study, we treated liver cancer cells with I3C, performed colony formation and cell migration, measured the expression of glycolysis-related proteins, and predicted and validated LDHA-targeting miRNA from the databases. In addition, the mRNA and protein levels of p53, glycolysis-related genes and miRNAs that regulate glycolysis were detected after I3C and siRNA-p53 treatment alone or in combination. Next, the expression and colocalization of p53 and MDM2 in liver cancer cells were evaluated after I3C treatment, and the effect of I3C on p53 protein stability was examined. The results showed that I3C inhibited cell proliferation, migration, and the expression levels of glycolysis-related gene LDHAs. MiR-34a was predicted to target LDHA, and I3C downregulated its expression. Furthermore, the combined I3C and siRNA-p53 treatment demonstrated that I3C regulated the expression of LDHA via miR-34a in a p53-dependent manner. Finally, I3C inhibited MDM2 expression and its colocalization with p53 and stabilized p53 expression. In summary, I3C inhibited the degradation of p53 by MDM2 in liver cancer cells; stable p53 induced miR-34a, which targeted LDHA, a key enzyme for aerobic glycolysis, suggesting cancer metabolism is an important target for I3C in liver cancer cells.

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Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells

Cited by 94 publications

References 57 publications

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle

Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells

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