Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

Méndez-Lucas, Andrés; Hyroššová, Petra; Novellasdemunt, Laura; Viñals, Francesc; Perales, José C.

doi:10.1074/jbc.m114.566927

Cited by 161 publications

(156 citation statements)

References 48 publications

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“…7F). These data are consistent with recent reports that glucose deprivation results in an increase in Pck expression (33, 34) which promotes metabolic flexibility when nutrients are limiting (35,36). Also, these data show the utility of assessing a phenotype across a series of genetic perturbations.…”

Section: Mpc Deficiency Promotes Metabolic Plasticity In Uterosupporting

confidence: 81%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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bGlucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. E mbryonic development in eutherian mammals is defined by ongoing metabolic interactions between mother and fetus. Placentas have evolved a sophisticated suite of adaptations to ensure adequate nutrient, gas, and waste exchange between fetus and mother, as well as hormonal and immunological communication (1, 2). To meet the fetal requirements for nutrient and oxygen consumption during pregnancy, maternal cardiac output increases such that uteroplacental blood flow accounts for ϳ25% of total cardiac output (3). Glucose and oxygen are arguably the two most important molecules transferred from mother to fetus, in terms of both concentration and the multitude of physiological adaptations in place to ensure their adequate transport; however, the requirement for mitochondrial oxidative metabolism during embryonic development remains poorly defined.While oxygen tension in utero is low relative to atmospheric levels, measurement of oxygen consumption and lactate uptake in fetal lambs provided evidence that the fetus is a net consumer rather than a producer of lactate (4). Consistent with this, fetal myocardium consumes a large amount of lactate, in addition to glucose, indicating that oxidative metabolism of carbohydrates is an important energy source in the developing heart (5, 6). Additionally, lactate utilization is high in the neonatal brain, and the capacity for lactate import is higher in the neonatal brain than in the adult brain (7). Together, these observations provide evidence for the importance of mitochondrial oxidative metabolism early in mammalian development. S...

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Section: Mpc Deficiency Promotes Metabolic Plasticity In Uterosupporting

confidence: 81%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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“…We further demonstrated that PCK2 limits cancer cell death under low glucose conditions and in 3D spheroids (3). Similar findings on PCK2 were obtained in breast, cervical, and colon carcinoma cells and published this year as well (4 …”

supporting

confidence: 71%

Gluconeogenesis in cancer: Door wide open

Leithner

Hrzenjak

Olschewski

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Posteriormente Qu et al (2016), informaron que el estrés calórico induce la expresión de la enzima fosfoenolpiruvato carboxiquinasa (PEPCK-C) en el tejido adiposo, provocando una elevación en la gliceroneogénesis, lo que podría explicar el aumento de la acumulación de grasa en los cerdos criados en ambiente con temperaturas elevadas. La fosfoenolpiruvato carboxiquinasa (PEPCK) se encuentra en dos isoformas (PEPCK-C y PEPCK-M); la PEPCKC se expresa principalmente en el hígado, el riñón y el tejido adiposo; en tanto que la PEPCK-M está presente en una variedad de tejidos no gluconeogénicos, incluyendo páncreas, cerebro, leucocitos, corazón o neuronas (Méndez-Lucas et al, 2014). En un estudio previo Méndez-Lucas et al (2013) concluyeron que la PEPCK-M tiene potencial gluconeogénico per se y coopera con la PEPCK-C para ajustar el flujo gluconeogénico a los cambios en la disponibilidad de sustrato o energía en el ciclo de Krebs, sugiriendo un papel en la regulación del metabolismo de glucosa y lípidos en el hígado.…”

Section: Resultados Y Discusiónunclassified

“…En un estudio previo Méndez-Lucas et al (2013) concluyeron que la PEPCK-M tiene potencial gluconeogénico per se y coopera con la PEPCK-C para ajustar el flujo gluconeogénico a los cambios en la disponibilidad de sustrato o energía en el ciclo de Krebs, sugiriendo un papel en la regulación del metabolismo de glucosa y lípidos en el hígado. Méndez-Lucas et al (2014) sugirieron que la PEPCK-M es importante para mantener la progresión y sobrevivencia celular bajo condiciones de estrés. Los resultados obtenidos en el presente estudio, sugieren que el mayor EGD observado en las cerdas que consumieron alimento adicionado con Met-Zn durante la época de calor, pudo estar influenciado por el Zn, mejorando la actividad enzimática en la síntesis y deposición de tejido adiposo.…”

Section: Resultados Y Discusiónunclassified

Efecto del consumo de zinc orgánico en la respuesta productiva de la cerda y su camada

et al. 2017

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Efecto del consumo de zinc orgánico en la respuesta productiva de la cerda y su camada Effect of organic zinc intake on the productive response of sows and their litter RESUMENPara evaluar la respuesta productiva de la cerda y su camada a la suplementación con zinc orgánico en clima tropical, se realizaron dos experimentos. Exp. 1 (Época fresca). Se utilizaron 46 cerdas Yorkshire x Landrace, asignadas a uno de dos tratamientos (T) en un diseño completamente al azar. T1 (SZn; n = 22); dieta sin adición de Zn a partir de los 35 días de gestación y durante 21 d de lactación; T2 (CZn; n = 24) T1 más la adición de 100 mg de Zn/kg de alimento. Exp. 2 (Época cálida). Se utilizaron 44 cerdas, asignadas al azar a uno de dos T similares al Exp.1: T1 (SZn; n = 25) y T2 (CZn; n = 19). Los resultados fueron analizados por ANDEVA (P ≤ 0.05). Resultados: Exp. 1. El consumo de alimento adicionado con Zn incrementó (P = 0.001) la concentración plasmática de IgG en los cerdos destetados. Exp. 2. El consumo de alimento adicionado con Zn, incrementó (P < 0.05) el espesor de grasa dorsal (EGD) de las cerdas durante la gestación (16.6 vs. 14.8 mm) y disminuyó (P = 0.006) la mortalidad durante la lactancia (11 vs. 26%). Se concluye que el consumo adicional de Zn incrementa el EGD en las cerdas gestantes bajo condiciones de estrés calórico y disminuye la mortalidad de lechones durante la lactancia, y el consumo adicional durante la época fresca incrementa los niveles plasmáticos de IgG en los LD. Palabras clave: Metionina de Zinc, Espesor de grasa dorsal, Mortalidad predestete. ABSTRACTTo evaluate the productive response of sows and their litter to the supplementation with zinc in a tropical climate two experiments were realized. Exp. 1 (Fresh season). 46 Yorkshire x Landrace sows were used, assigned to one of two treatments (T) in a completely randomized design. T1 (SZn; n = 22); diet without addition of Zn from 35 days of gestation and during 21 d of lactation, and T2 (CZn; n = 24), T1 diet plus supplementation with 100 mg Zn/kg of feed. Exp. 2 (Warm season). Another 44 sows were assigned to one of two treatments similar to Exp. 1. T1 (SZn; n = 25) and T2 (CZn; n = 19). Results were analyzed by ANOVA (P ≤ 0.05). Results: Exp. 1. Feed consumption added with Zn increased (P < 0.05) IgG plasmatic concentration in weaned pigs. Exp. 2. Feed consumption added with Zn increased (P < 0.05) backfat thickness (BFT) of the sows during the gestation (16.6 vs. 14.8 mm) and decreased (P = 0.006) the mortality of nursing pigs during the lactation (11 vs. 26%). It concludes that additional consumption of zinc increase the BFT in gestating sows under environment heat stress and diminished the mortality of nursing pigs during lactation and intake of supplemented diet with zinc during fresh season increase IgG plasmatic concentration levels in weaned pigs.

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Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

Cited by 161 publications

References 48 publications

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Gluconeogenesis in cancer: Door wide open

Efecto del consumo de zinc orgánico en la respuesta productiva de la cerda y su camada

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