A Role for the Mitochondrial Pyruvate Carrier as a Repressor of the Warburg Effect and Colon Cancer Cell Growth

Schell, John C.; Olson, Kristofor A.; Jiang, Lei; Hawkins, A. B.; Vranken, Jonathan G. Van; Xie, Jingui; Egnatchik, Robert A.; Earl, Espen G.; DeBerardinis, Ralph J.; Rutter, Jared

doi:10.1016/j.molcel.2014.09.026

Cited by 317 publications

(394 citation statements)

References 73 publications

(77 reference statements)

Supporting

Mentioning

352

Contrasting

Unclassified

Order By: Relevance

“…A decrease in MPC activity has been shown to perturb whole body glucose homeostasis through effects on glucose-stimulated insulin secretion (11,12) and gluconeogenesis (13,14). In addition, reduced MPC expression (15,16) and activity (17)(18)(19) has been observed in cancer cells, contributing to the Warburg effect. This favors cell growth and metastasis and promotes the establishment and maintenance of the cancer stem cell compartment (15,16,20).…”

mentioning

confidence: 99%

See 1 more Smart Citation

MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells

Vanderperre¹,

Cermakova²,

Escoffier

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Selective transport of pyruvate across the inner mitochondrial membrane by the mitochondrial pyruvate carrier (MPC) is a fundamental step that couples cytosolic and mitochondrial metabolism. The recent molecular identification of the MPC complex has revealed two interacting subunits, MPC1 and MPC2. Although in yeast, an additional subunit, MPC3, can functionally replace MPC2, no alternative MPC subunits have been described in higher eukaryotes. Here, we report for the first time the existence of a novel MPC subunit termed MPC1-like (MPC1L), which is present uniquely in placental mammals. MPC1L shares high sequence, structural, and topological homology with MPC1. In addition, we provide several lines of evidence to show that MPC1L is functionally equivalent to MPC1: 1) when co-expressed with MPC2, it rescues pyruvate import in a MPC-deleted yeast strain; 2) in mammalian cells, it can associate with MPC2 to form a functional carrier as assessed by bioluminescence resonance energy transfer; 3) in MPC1 depleted mouse embryonic fibroblasts, MPC1L rescues the loss of pyruvate-driven respiration and stabilizes MPC2 expression; and 4) MPC1-and MPC1L-mediated pyruvate imports show similar efficiency. However, we show that MPC1L has a highly specific expression pattern and is localized almost exclusively in testis and more specifically in postmeiotic spermatids and sperm cells. This is in marked contrast to MPC1/MPC2, which are ubiquitously expressed throughout the organism. To date, the biological importance of this alternative MPC complex during spermatogenesis in placental mammals remains unknown. Nevertheless, these findings open up new avenues for investigating the structure-function relationship within the MPC complex.The metabolic balance between glycolysis and oxidative phosphorylation (OXPHOS) 2 is of crucial importance in determining cell function and fate. Rapidly proliferating cells rely preferentially on glycolysis despite its lower yield of ATP, because glycolytic intermediates efficiently meet the anabolic needs for sustained cell growth. In rapidly dividing cells, this occurs even in the presence of oxygen, a process called aerobic glycolysis, or the Warburg effect (1, 2). Differentiated cells rely more heavily on OXPHOS to meet the energy demands associated with their specialization. In addition, a shift from glycolytic to oxidative metabolism is necessary for the differentiation process to occur (2-4), and conversely, a hallmark of cancer lies in the rewiring of cellular metabolism toward increased glycolytic flux (5). Pyruvate, the end product of glycolysis, is imported into the mitochondrial matrix where it fuels the TCA cycle and thereby provides electrons and reducing equivalents to the respiratory chain. Pyruvate-derived acetyl-CoA can also be used as an anabolic substrate for the synthesis of lipids and amino acids. Thus, elucidating the molecular mechanisms that determine the intracellular fate of pyruvate is important for understanding the control of cell metabolism and ultimately of cell funct...

show abstract

mentioning

confidence: 99%

“…In addition, reduced MPC expression (15,16) and activity (17)(18)(19) has been observed in cancer cells, contributing to the Warburg effect. This favors cell growth and metastasis and promotes the establishment and maintenance of the cancer stem cell compartment (15,16,20).…”

mentioning

confidence: 99%

MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells

Vanderperre¹,

Cermakova²,

Escoffier

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This conserved protein complex is responsible for transporting pyruvate into the mitochondrial matrix and represents the key metabolic link between glycolysis and oxidative phosphorylation (Bricker et al, 2012). Consistent with Warburg's observations, the Rutter lab found that many cancers exhibit decreased MPC1 expression, which results in an enhanced glycolytic state and increased tumor growth (Schell et al, 2014). Furthermore, Rutter also described unpublished data which reveal that the MPC promotes stem cell proliferation in the intestine, thereby implicating MPC as a key developmental regulator.…”

Section: New Roles For the Warburg Effectmentioning

confidence: 70%

Metabolism in time and space – exploring the frontier of developmental biology

Krejčı́

Tennessen

2017

Development

View full text Add to dashboard Cite

Despite the fact that metabolic studies played a prominent role in the early history of developmental biology research, the field of developmental metabolism was largely ignored following the advent of modern molecular biology. Metabolism, however, has recently re-emerged as a focal point of biomedical studies and, as a result, developmental biologists are once again exploring the chemical and energetic forces that shape growth, development and maturation. In May 2017, a diverse group of scientists assembled at the EMBO/ EMBL Symposium 'Metabolism in Time and Space' to discuss how metabolism influences cellular and developmental processes. The speakers not only described how metabolic flux adapts to the energetic needs of a developing organism, but also emphasized that metabolism can directly regulate developmental progression. Overall, and as we review here, this interdisciplinary meeting provided a valuable forum to explore the interface between developmental biology and metabolism.

show abstract

“…Alternative explanations for the effect include decrease pyruvate production by PKM2, upregulated LDH and increase expression of PDH kinase PDK1. Rutter's group now showed that impaired mitochondrial transport due to MPC1 deletion or diminished expression could also explain the Warburg effect [33]. The authors found that while the gene locus of MPC2 is not frequently loss or altered in cancer, the MPC1 locus is within the most frequently deleted region across all cancer samples investigated.…”

Section: Mpc Mitochondrial Pyruvate Transport and Cancermentioning

confidence: 99%

The Mitochondrial Pyruvate Carrier and Metabolic Regulation

Tang

2014

CellBio

View full text Add to dashboard Cite

Pyruvate is a key intermediate at the branchpoint of anaerobic and aerobic energy metabolism. Its transport into the mitochondrial matrix is necessary prior to its decarboxylation into acetyl-CoA, which feeds the reducing equivalent-generating tricarboxylic acid (TCA) cycle. Although the existence of specific carrier transport of cytosolic pyruvate into the mitochondria has been inferred from a myriad of studies, the identities of the mitochondrial pyruvate carrier (MPC) were only confirmed very recently. Identification of the MPC facilitated several other recent advances. These include the finding of MPC's inhibition by the insulin-sensitizing drug family thiazolidinediones, how cells respond flexibly to a reduction in MPC functionality, as well as insights into how changes in MPC levels affect oncogenic potential of cancer cells. These new findings, discussed here in this brief review, have important implications in therapeutic approaches towards metabolic disorders and cancer.

show abstract

A Role for the Mitochondrial Pyruvate Carrier as a Repressor of the Warburg Effect and Colon Cancer Cell Growth

Cited by 317 publications

References 73 publications

MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells

MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells

Metabolism in time and space – exploring the frontier of developmental biology

The Mitochondrial Pyruvate Carrier and Metabolic Regulation

Contact Info

Product

Resources

About