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Chicken or the egg: Warburg effect and mitochondrial dysfunction.

Senyilmaz D, Teleman AA - F1000Prime Rep (2015)

Bottom Line: However, this hypothesis did not convince every scientist in the field.Some believed the opposite: the reduction in mitochondrial activity is a result of increased glycolysis.This discrepancy of opinions is ongoing.

View Article: PubMed Central - PubMed

Affiliation: German Cancer Research Center (DKFZ) Heidelberg Germany.

ABSTRACT
Compared with normal cells, cancer cells show alterations in many cellular processes, including energy metabolism. Studies on cancer metabolism started with Otto Warburg's observation at the beginning of the last century. According to Warburg, cancer cells rely on glycolysis more than mitochondrial respiration for energy production. Considering that glycolysis yields much less energy compared with mitochondrial respiration, Warburg hypothesized that mitochondria must be dysfunctional and this is the initiating factor for cancer formation. However, this hypothesis did not convince every scientist in the field. Some believed the opposite: the reduction in mitochondrial activity is a result of increased glycolysis. This discrepancy of opinions is ongoing. In this review, we will discuss the alterations in glycolysis, pyruvate metabolism, and the Krebs cycle in cancer cells and focus on cause and consequence.

No MeSH data available.


Related in: MedlinePlus

Krebs cycle reactions are altered but not completely abrogated in cancer cells(A) Full Krebs cycle in the presence of functional mitochondria and oxygen. Cancer cells use glutamine more than pyruvate for anaplerosis. (B) A truncated form of the Krebs cycle is favored in cancer cells with defective mitochondria or under hypoxic conditions (or both) to generate metabolic precursors with reductive carboxylation. 2-HG, 2-hydroxyglutarate; AcCoA, acetyl coenzyme A; ACL, ATP citrate lyase; ASCT2, sodium-dependent neutral amino acid transporter type 2; CS, citrate synthase; DCA, dichloroacetate; FA, fatty acid; FAD, flavin adenine dinucleotide; FH, fumarate hydratase; GLS, glutaminase; HIF1, hypoxia-induced factor 1; IDH, isocitrate dehydrogenase; ME, malic enzyme; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; pyr, pyruvate; SDH, succinate dehydrogenase.
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fig-003: Krebs cycle reactions are altered but not completely abrogated in cancer cells(A) Full Krebs cycle in the presence of functional mitochondria and oxygen. Cancer cells use glutamine more than pyruvate for anaplerosis. (B) A truncated form of the Krebs cycle is favored in cancer cells with defective mitochondria or under hypoxic conditions (or both) to generate metabolic precursors with reductive carboxylation. 2-HG, 2-hydroxyglutarate; AcCoA, acetyl coenzyme A; ACL, ATP citrate lyase; ASCT2, sodium-dependent neutral amino acid transporter type 2; CS, citrate synthase; DCA, dichloroacetate; FA, fatty acid; FAD, flavin adenine dinucleotide; FH, fumarate hydratase; GLS, glutaminase; HIF1, hypoxia-induced factor 1; IDH, isocitrate dehydrogenase; ME, malic enzyme; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; pyr, pyruvate; SDH, succinate dehydrogenase.

Mentions: The second possibility of pyruvate utilization is to send it to mitochondria for further oxidation in the Krebs cycle. The limiting step here is the entry of pyruvate into mitochondria by mitochondrial pyruvate carriers (MPCs) (Figure 2). The activity and chemical inhibition of a MPC were shown in 1974 [63], but the molecular identities of these carriers remained a secret until 2012, when they were identified as MPC1 and MPC2 [64,65]. The cancer relevance of these carriers was thoroughly investigated very recently [66–68]. In MPC1 loss-of-function tumor models, forced expression of the protein leads to activation of mitochondrial pyruvate oxidation, which inhibits anchorage-independent growth of colon cancer cells [68]. These studies indicate that MPC loss of function could be one means of rewiring cancer metabolism toward aerobic glycolysis, the Warburg effect. In tumor types with reduced MPC activity, it could be used as a therapeutic target. The fact that forced activation of MPC can activate mitochondrial respiration suggests that mitochondria are not necessarily irreversibly damaged, as Warburg claimed. Upon entry into mitochondria, pyruvate is converted to acetyl coenzyme A (CoA) and joins the Krebs cycle, during which reduced nicotinamide adenine dinucleotide (NADH) and precursors for anabolic pathways are generated (Figure 3A).


Chicken or the egg: Warburg effect and mitochondrial dysfunction.

Senyilmaz D, Teleman AA - F1000Prime Rep (2015)

Krebs cycle reactions are altered but not completely abrogated in cancer cells(A) Full Krebs cycle in the presence of functional mitochondria and oxygen. Cancer cells use glutamine more than pyruvate for anaplerosis. (B) A truncated form of the Krebs cycle is favored in cancer cells with defective mitochondria or under hypoxic conditions (or both) to generate metabolic precursors with reductive carboxylation. 2-HG, 2-hydroxyglutarate; AcCoA, acetyl coenzyme A; ACL, ATP citrate lyase; ASCT2, sodium-dependent neutral amino acid transporter type 2; CS, citrate synthase; DCA, dichloroacetate; FA, fatty acid; FAD, flavin adenine dinucleotide; FH, fumarate hydratase; GLS, glutaminase; HIF1, hypoxia-induced factor 1; IDH, isocitrate dehydrogenase; ME, malic enzyme; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; pyr, pyruvate; SDH, succinate dehydrogenase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4447048&req=5

fig-003: Krebs cycle reactions are altered but not completely abrogated in cancer cells(A) Full Krebs cycle in the presence of functional mitochondria and oxygen. Cancer cells use glutamine more than pyruvate for anaplerosis. (B) A truncated form of the Krebs cycle is favored in cancer cells with defective mitochondria or under hypoxic conditions (or both) to generate metabolic precursors with reductive carboxylation. 2-HG, 2-hydroxyglutarate; AcCoA, acetyl coenzyme A; ACL, ATP citrate lyase; ASCT2, sodium-dependent neutral amino acid transporter type 2; CS, citrate synthase; DCA, dichloroacetate; FA, fatty acid; FAD, flavin adenine dinucleotide; FH, fumarate hydratase; GLS, glutaminase; HIF1, hypoxia-induced factor 1; IDH, isocitrate dehydrogenase; ME, malic enzyme; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; pyr, pyruvate; SDH, succinate dehydrogenase.
Mentions: The second possibility of pyruvate utilization is to send it to mitochondria for further oxidation in the Krebs cycle. The limiting step here is the entry of pyruvate into mitochondria by mitochondrial pyruvate carriers (MPCs) (Figure 2). The activity and chemical inhibition of a MPC were shown in 1974 [63], but the molecular identities of these carriers remained a secret until 2012, when they were identified as MPC1 and MPC2 [64,65]. The cancer relevance of these carriers was thoroughly investigated very recently [66–68]. In MPC1 loss-of-function tumor models, forced expression of the protein leads to activation of mitochondrial pyruvate oxidation, which inhibits anchorage-independent growth of colon cancer cells [68]. These studies indicate that MPC loss of function could be one means of rewiring cancer metabolism toward aerobic glycolysis, the Warburg effect. In tumor types with reduced MPC activity, it could be used as a therapeutic target. The fact that forced activation of MPC can activate mitochondrial respiration suggests that mitochondria are not necessarily irreversibly damaged, as Warburg claimed. Upon entry into mitochondria, pyruvate is converted to acetyl coenzyme A (CoA) and joins the Krebs cycle, during which reduced nicotinamide adenine dinucleotide (NADH) and precursors for anabolic pathways are generated (Figure 3A).

Bottom Line: However, this hypothesis did not convince every scientist in the field.Some believed the opposite: the reduction in mitochondrial activity is a result of increased glycolysis.This discrepancy of opinions is ongoing.

View Article: PubMed Central - PubMed

Affiliation: German Cancer Research Center (DKFZ) Heidelberg Germany.

ABSTRACT
Compared with normal cells, cancer cells show alterations in many cellular processes, including energy metabolism. Studies on cancer metabolism started with Otto Warburg's observation at the beginning of the last century. According to Warburg, cancer cells rely on glycolysis more than mitochondrial respiration for energy production. Considering that glycolysis yields much less energy compared with mitochondrial respiration, Warburg hypothesized that mitochondria must be dysfunctional and this is the initiating factor for cancer formation. However, this hypothesis did not convince every scientist in the field. Some believed the opposite: the reduction in mitochondrial activity is a result of increased glycolysis. This discrepancy of opinions is ongoing. In this review, we will discuss the alterations in glycolysis, pyruvate metabolism, and the Krebs cycle in cancer cells and focus on cause and consequence.

No MeSH data available.


Related in: MedlinePlus