scholarly journals Heart failure—emerging roles for the mitochondrial pyruvate carrier

2021 ◽  
Author(s):  
Mariana Fernandez-Caggiano ◽  
Philip Eaton
Keyword(s):  
Heart Failure ◽  
Warburg Effect ◽  
Translational Regulation ◽  
Hypertrophic Growth ◽  
Metabolic Adaptations ◽  
Mitochondrial Pyruvate Carrier ◽  
Heart Failure Progression ◽  
Mitochondrial Oxidation ◽  
Human And Mouse ◽  
The Warburg Effect

AbstractThe mitochondrial pyruvate carrier (MPC) is the entry point for the glycolytic end-product pyruvate to the mitochondria. MPC activity, which is controlled by its abundance and post-translational regulation, determines whether pyruvate is oxidised in the mitochondria or metabolised in the cytosol. MPC serves as a crucial metabolic branch point that determines the fate of pyruvate in the cell, enabling metabolic adaptations during health, such as exercise, or as a result of disease. Decreased MPC expression in several cancers limits the mitochondrial oxidation of pyruvate and contributes to lactate accumulation in the cytosol, highlighting its role as a contributing, causal mediator of the Warburg effect. Pyruvate is handled similarly in the failing heart where a large proportion of it is reduced to lactate in the cytosol instead of being fully oxidised in the mitochondria. Several recent studies have found that the MPC abundance was also reduced in failing human and mouse hearts that were characterised by maladaptive hypertrophic growth, emulating the anabolic scenario observed in some cancer cells. In this review we discuss the evidence implicating the MPC as an important, perhaps causal, mediator of heart failure progression.

scholarly journals Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect

2015 ◽  
Vol 59 (3) ◽  
pp. 491-501 ◽  
Author(s):  
Vincent Compan ◽  
Sandra Pierredon ◽  
Benoît Vanderperre ◽  
Petra Krznar ◽  
Ibtissam Marchiq ◽  
...  
Keyword(s):  
Real Time ◽  
Warburg Effect ◽  
Mitochondrial Pyruvate Carrier ◽  
The Warburg Effect

scholarly journals Translating Translation to Mechanisms of Cardiac Hypertrophy

2020 ◽  
Vol 7 (1) ◽  
pp. 9 ◽  
Author(s):  
Michael J. Zeitz ◽  
James W. Smyth
Keyword(s):  
Heart Failure ◽  
Protein Synthesis ◽  
Heart Disease ◽  
Cardiac Hypertrophy ◽  
Translational Regulation ◽  
Molecular Mechanisms ◽  
Clinical Investigation ◽  
Translational Machinery ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy

Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation.

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

2014 ◽  
Vol 56 (3) ◽  
pp. 400-413 ◽  
Author(s):  
John C. Schell ◽  
Kristofor A. Olson ◽  
Lei Jiang ◽  
Amy J. Hawkins ◽  
Jonathan G. Van Vranken ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Warburg Effect ◽  
Colon Cancer Cell ◽  
Cancer Cell Growth ◽  
Mitochondrial Pyruvate Carrier ◽  
The Warburg Effect

scholarly journals Loss of MPC1 reprograms retinal metabolism to impair visual function

2019 ◽  
Vol 116 (9) ◽  
pp. 3530-3535 ◽  
Author(s):  
Allison Grenell ◽  
Yekai Wang ◽  
Michelle Yam ◽  
Aditi Swarup ◽  
Tanya L. Dilan ◽  
...  
Keyword(s):  
Visual Function ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Reducing Power ◽  
Glutamate Metabolism ◽  
Targeted Metabolomics ◽  
Mitochondrial Pyruvate Carrier ◽  
Rod And Cone Photoreceptors ◽  
Specific Deletion ◽  
The Warburg Effect

Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the “Warburg Effect”), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the small fraction of pyruvate in photoreceptors that does get oxidized by their mitochondria is required for visual function, photoreceptor structure and viability, normal neuron–glial interaction, and homeostasis of retinal metabolism. The mitochondrial pyruvate carrier (MPC) links glycolysis and mitochondrial metabolism. Retina-specific deletion of MPC1 results in progressive retinal degeneration and decline of visual function in both rod and cone photoreceptors. Using targeted-metabolomics and 13C tracers, we found that MPC1 is required for cytosolic reducing power maintenance, glutamine/glutamate metabolism, and flexibility in fuel utilization.

The warburg effect and tumour cell survival in human GBMs

2007 ◽  
Vol 30 (4) ◽  
pp. 97 ◽  
Author(s):  
A Wolf ◽  
J Mukherjee ◽  
A Guha
Keyword(s):  
Cytochrome C ◽  
Cell Survival ◽  
Expression Profile ◽  
Tumour Cell ◽  
Warburg Effect ◽  
Glycolytic Enzymes ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
The Warburg Effect

Introduction: GBMs are resistant to apoptosis induced by the hypoxic microenvironment and standard therapies including radiation and chemotherapy. We postulate that the Warburg effect, a preferential glycolytic phenotype of tumor cells even under aerobic conditions, plays a role in these aberrant pro-survival signals. In this study we quantitatively examined the expression profile of hypoxia-related glycolytic genes within pathologically- and MRI-defined “centre” and “periphery” of GBMs. We hypothesize that expression of hypoxia-induced glycolytic genes, particularly hexokinase 2 (HK2), favours cell survival and modulates resistance to tumour cell apoptosis by inhibiting the intrinsic mitochondrial apoptotic pathway. Methods: GBM patients underwent conventional T1-weighted contrast-enhanced MRI and MR spectroscopy studies on a 3.0T GE scanner, prior to stereotactic sampling (formalin and frozen) from regions which were T1-Gad enhancing (“centre”) and T2-positive, T1-Gad negative (“periphery”). Real-time qRT-PCR was performed to quantify regional gene expression of glycolytic genes including HK2. In vitro functional studies were performed in U87 and U373 GBM cell lines grown in normoxic (21% pO2) and hypoxic (< 1%pO2) conditions, transfected with HK2 siRNA followed by measurement of cell proliferation (BrdU), apoptosis (activated caspase 3/7, TUNEL, cytochrome c release) and viability (MTS assay). Results: There exists a differential expression profile of glycolytic enzymes between the hypoxic center and relatively normoxic periphery of GBMs. Under hypoxic conditions, there is increased expression of HK2 at the mitochondrial membrane in GBM cells. In vitro HK2 knockdown led to decreased cell survival and increased apoptosis via the intrinsic mitochondrial pathway, as seen by increased mitochondrial release of cytochrome-C. Conclusions: Increased expression of HK2 in the centre of GBMs promotes cell survival and confers resistance to apoptosis, as confirmed by in vitro studies. In vivo intracranial xenograft studies with injection of HK2-shRNA are currently being performed. HK2 and possibly other glycolytic enzymes may provide a target for enhanced therapeutic responsiveness thereby improving prognosis of patients with GBMs.

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