Hexokinase I expression and activity in embryonic mouse heart during early and late organogenesis

Fritz, Heidi; Smoak, Ida W.; Branch, Stacy

doi:10.1007/s004180050417

Cited by 21 publications

(15 citation statements)

References 18 publications

(18 reference statements)

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“…Indeed, cardiomyocytes had higher Hxk-1 protein content with a dappled pattern of intracellular localization corresponding to mitochondrial network arrangement throughout the cell and specifically in the intermyofibrillar space. This data is in line with the demonstration that Hxk-1 is localized mainly in the heart at early stages of embryonic development [23]. Although adult cardiomyocytes display both Hxk-1 and Hxk-2 isoforms, Hxk-2 is predominant [40].…”

Section: Discussionsupporting

confidence: 88%

Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation

Chung

Arrell

Faustino

et al. 2010

Journal of Molecular and Cellular Cardiology

152

139

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Decoding of the bioenergetic signature underlying embryonic stem cell cardiac differentiation has revealed a mandatory transformation of the metabolic infrastructure with prominent mitochondrial network expansion, and a distinctive switch from glycolysis to oxidative phosphorylation. Here, we demonstrate that despite reduction in total glycolytic capacity, stem cell cardiogenesis engages a significant transcriptome, proteome, as well as enzymatic and topological rearrangement in the proximal, medial, and distal modules of the glycolytic pathway. Glycolytic restructuring was manifested by a shift in hexokinase (Hk) isoforms from Hk-2 to cardiac Hk-1, with intracellular and intermyofibrillar localization mapping mitochondrial network arrangement. Moreover, upregulation of cardiac specific enolase 3, phosphofructokinase, phosphoglucomutase and a marked increase in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) phosphotransfer activity, along with apparent post-translational modifications of GAPDH and phosphoglycerate kinase, were all distinctive for derived cardiomyocytes compared to the embryonic stem cell source. Lactate dehydrogenase (LDH) isoforms evolved towards LDH-2 and LDH-3, containing higher proportions of heart-specific subunits, and pyruvate dehydrogenase isoforms rearranged between E1α and E1β, transitions favorable for substrate oxidation in mitochondria. Concomitantly, transcript levels of fetal pyruvate kinase isoform M2, aldolase 3 and transketolase, which shunt the glycolytic with pentose phosphate pathways, were reduced. Collectively, changes in glycolytic pathway modules indicate active redeployment which would facilitate connectivity of the expanding mitochondrial network with ATP utilization sites. Thus, the delineated developmental dynamics of the glycolytic phosphotransfer network is integral to the remodeling of cellular energetic infrastructure underlying stem cell cardiogenesis. Keywordsbioenergetics; cardiogenesis; embryonic stem cells; proteomics; transcriptome Robust developmental transitions in the bioenergetic system highlights embryonic stem (ES) cell differentiation into the energy-demanding cardiac phenotype, characterized by a switch *Correspondence at Mayo Clinic, 200 First Street SW, Stabile 5, Rochester, MN 55905, USA. dzeja.petras@mayo.edu; terzic.andre@mayo.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript from glycolytic to oxidative energy metabolism with expansion and maturation of the mitochondrial network [1][2][3]. Extensive...

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Section: Discussionsupporting

confidence: 88%

Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation

Chung

Arrell

Faustino

et al. 2010

Journal of Molecular and Cellular Cardiology

152

139

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“…Error bars represent SEM. * Different from gd 9.5 value at P<0.02 early (gd 9.5) versus late (gd 13.5) organogenesis (Fritz et al 1999). The facilitated diffusion of glucose across the plasma membrane is the rate-limiting step for subsequent glucose utilization and is mediated by a family of Glut proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Glycolytic metabolism and hexokinase activity are approximately six-and two-fold higher, respectively, in embryonic hearts during early (gd 9.5) versus late (gd 13.5) organogenesis (Fritz et al 1999). The importance of glucose to heart function during early organogenesis has also been demonstrated in rat embryos exposed to anaerobic conditions and metabolic inhibitors (Cox and Gunberg 1972).…”

Section: Introductionmentioning

confidence: 85%

Glut-1 expression and its response to hypoglycemia in the embryonic mouse heart

Smoak¹,

Branch

2000

Anatomy and Embryology

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The embryonic heart depends on glucose during early organogenesis. Glut-1 functions in constitutive glucose uptake in adult tissues and is the predominant glucose transporter in embryonic and fetal tissues. This study focuses on Glut-1 expression in the heart during normal organogenesis using immunohistochemistry for Glut-1 distribution, Western analysis for Glut-1 protein levels, and reverse transcriptase polymerase chain reaction for Glut-1 mRNA levels. The role of Glut in glucose uptake response to hypoglycemia in the embryonic heart is evaluated using the Glut inhibitor cytochalasin B. Cardiac Glut-1 expression is also evaluated after in vitro hypoglycemic exposure. Glut-1 levels are highest on gestational days 9-10, intermediate on gestational day 10.5, and lowest on gestational days 11.5-13.5 in the normal embryonic heart. Cardiac Glut-1 mRNA levels similarly decline between gestational days 9.5 and gd 13.5. Cytochalasin B produces a dose-dependent decrease in glucose uptake in hearts exposed to hypoglycemia for 30 min or 6 h, implicating Glut in this response. Glut-1 protein expression is unchanged after 2 or 6 h but increased after 12 and 24 h of hypoglycemia in the gestational day 9.5 heart. Thus, Glut-1 expression is prominent in the embryonic heart and is correlated with changes in cardiac glucose requirements during normal organogenesis. Glut activity increases in response to acute hypoglycemia and the expression of Glut-1 increases in response to prolonged hypoglycemia. These results support the importance of Glut-1 during normal cardiogenesis and in response to hypoglycemia in the embryonic heart.

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“…Even after birth, as mitochondrial metabolism matures, glycolysis is still the preferred energetic pathway for several weeks, driven in part by expression of insulin-independent isoforms of the glucose transporter (GLUT1) and HKI, with its strong binding to mitochondria. Thus, HKI is the predominant isoform in embryonic, fetal and neonatal hearts [115] facilitating their high glycolytic rate [30]. After birth, the transition from a continuous supply of placental glucose to an intermittent mixed carbohydrate-fat oral diet during nursing, induces a switch to the insulin-dependent isoforms GLUT4 and HK2 [30, 116], along with down-regulation of other glycolytic enzymes and upregulation of oxidative phosphorylation enzymes [117].…”

Section: Hk and Metabolic Profiles In Cancer Developing Hearts And mentioning

confidence: 99%

Hexokinases and cardioprotection

Calmettes¹,

Ribalet²,

John³

et al. 2015

Journal of Molecular and Cellular Cardiology

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As mediators of the first enzymatic step in glucose metabolism, hexokinases (HKs) orchestrate a variety of catabolic and anabolic uses of glucose, regulate antioxidant power by generating NADPH for glutathione reduction, and modulate cell death processes by directly interacting with the voltage-dependent anion channel (VDAC), a regulatory component of the mitochondrial permeability transition pore (mPTP). Here we summarize the current state-of-knowledge about HKs and their role in protecting the heart from ischemia/reperfusion (I/R) injury, reviewing: 1) the properties of different HK isoforms and how their function is regulated by their subcellular localization; 2) how HKs modulate glucose metabolism and energy production during I/R; 3) the molecular mechanisms by which HKs influence mPTP opening and cellular injury during I/R; 4) how different metabolic and HK profiles correlate with susceptibility to I/R injury and cardioprotective efficacy in cancer cells, neonatal hearts, and normal, hypertrophied and failing adult hearts, and how these difference may guide novel therapeutic strategies to limit I/R injury in the heart.

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Hexokinase I expression and activity in embryonic mouse heart during early and late organogenesis

Cited by 21 publications

References 18 publications

Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation

Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation

Glut-1 expression and its response to hypoglycemia in the embryonic mouse heart

Hexokinases and cardioprotection

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