Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells

Wu, Min; Neilson, Andy; Swift, Amy L.; Moran, Rebecca; Tamagnine, James; Parslow, Diane; Armistead, Suzanne; Lemire, Kristie; Orrell, Jim; Teich, Jay; Chomicz, Steve; Ferrick, David A.

doi:10.1152/ajpcell.00247.2006

Cited by 813 publications

(772 citation statements)

References 38 publications

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“…ATP production by glycolysis is considered to have a 1:1 ratio with lactate production. The extracellular acidification rate is mainly due to lactate and bicarbonate production and, when calibrated as the proton production rate, indicates glycolytic rate (Birket et al 2011; Wu et al , 2007). Data are mean ± SD, n = 4 technical repeats (representative of two independent experiments).…”

Section: Resultsmentioning

confidence: 99%

Mitochondria are required for pro‐ageing features of the senescent phenotype

et al. 2016

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Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.

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Section: Resultsmentioning

confidence: 99%

Mitochondria are required for pro‐ageing features of the senescent phenotype

et al. 2016

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“…After releasing for 2.5, 6.5, and 11.5 hours, the cells were equilibrated with DMEM without bicarbonate (Seahorse Bioscience) in a non-CO 2 incubator at 37 C for 30 minutes. Extracellular acidification rate (ECAR) were recorded simultaneously by using a Seahorse Bioscience XF24 plate reader at 3, 7, and 12 hours after releasing, according to the manufacturer's instruction (8).…”

Section: Extracellular Acidification Ratementioning

confidence: 99%

“…On the other hand, previous works have shown that mitochondrial oxidative phosphorylation has key roles in cell-cycle progression (8). Progression of G 1 phase in Jurkat cells was shown to be correlated with activation of respiration (9).…”

Section: Introductionmentioning

confidence: 97%

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Bao

Mukai

Hishiki

et al. 2013

Molecular Cancer Research

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Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cellcycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phasedependent fluorescent marker Fucci to distinguish cells in G 1 -phase and those in S þ G 2 /M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G 1 -phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G 2 -M phases, suggesting accelerated glycolysis in G 1 -phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G 2 -M, and G 1 phases suggested that efflux of lactate was elevated significantly in G 1 -phase. By contrast, ATP production in G 2 -M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G 1 and G 2 -M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G 2 -M to G 1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973-85. Ó2013 AACR.

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“…49,50 Briefly, 4.0 Â 10 5 Z138 cells/well were adhered to XF 24-well cell culture microplates (Seahorse Biosciences) using BD Cell-Tak (BD Biosciences, Oxfordshire, UK) and plates incubated at 37 1C for 1 h before OCR and ECAR analysis. FCCP and rotenone were loaded into drug delivery ports and added sequentially at the indicated time points.…”

Section: Cell Metabolism Assaysmentioning

confidence: 99%

Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL

et al. 2012

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TRAIL (TNF (tumour necrosis factor)-related apoptosis-inducing ligand) a putative anti-cancer cytokine induces apoptosis through DISC (death-inducing signalling complex)-mediated activation of caspase-8 and/or cleavage of Bid. TRAIL is relatively specific for tumour cells but primary chronic lymphocytic leukaemia and mantle cell lymphoma (MCL) cells are resistant. Herein, we show that cellular metabolism influences cell death and that MCL cells (Z138 cell line) can survive/proliferate in glucose-free media by switching from aerobic glycolysis to 'coupled' oxidative phosphorylation. Extracellular flux analysis and mitochondrial inhibitors reveal that in the absence of glycolysis, Z138 cells have enhanced respiratory capacity coupled to ATP synthesis, similar to 'classical' state 3 mitochondria. Conversely, 2-deoxyglucose (2DG) blocked glycolysis and partially inhibited glycolyticdependent oxidative phosphorylation, resulting in a 50% reduction in cellular ATP levels. Also, 2DG sensitised Z138 cells to TRAIL and induced a marked decrease in caspase-8, -3, cFLIP S , Bid and Mcl-1 expression but Bak remained unchanged, altering the Mcl-1/Bak ratio, facilitating cytochrome c release and cell death. Conversely, under glucose-free conditions, Z138 cells were less sensitive to TRAIL with reduced TRAIL-R1/R2 surface receptor expression and impaired DISC formation. Anti-apoptotic proteins Bcl-2 and XIAP were up-regulated while pro-apoptotic BAX was down-regulated. Additionally, mitochondria had higher levels of cytochrome c and ultrastucturally exhibited a condensed configuration with enhanced intracristal spaces. Thus, metabolic switching was accompanied by mitochondrial proteome and ultrastructural remodelling enabling enhanced respiration activity. Cytochrome c release was decreased in glucose-free cells, suggesting that either pore formation was inhibited or that cytochrome c was more tightly bound. Glucose-free Z138 cells were also resistant to intrinsic cell death stimuli (ABT-737 and ionising radiation). In summary, in MCL cells, the anti-glycolytic effects of 2DG and glucose restriction produced opposite effects on TRAIL-induced cell death, demonstrating that mitochondrial metabolism directly modulates sensitivity of tumour cells to apoptosis.

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Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells

Cited by 813 publications

References 38 publications

Mitochondria are required for pro‐ageing features of the senescent phenotype

Mitochondria are required for pro‐ageing features of the senescent phenotype

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL

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