Allosteric, transcriptional and post-translational control of mitochondrial energy metabolism

2019 ◽  
Vol 476 (12) ◽  
pp. 1695-1712 ◽  
Author(s):  
Qutuba G. Karwi ◽  
Alice R. Jörg ◽  
Gary D. Lopaschuk
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Energy Production ◽  
Energy Regulation ◽  
Energy Substrates ◽  
Mitochondrial Energy Metabolism ◽  
Atp Production ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

AbstractThe heart is the organ with highest energy turnover rate (per unit weight) in our body. The heart relies on its flexible and powerful catabolic capacity to continuously generate large amounts of ATP utilizing many energy substrates including fatty acids, carbohydrates (glucose and lactate), ketones and amino acids. The normal health mainly utilizes fatty acids (40–60%) and glucose (20–40%) for ATP production while ketones and amino acids have a minor contribution (10–15% and 1–2%, respectively). Mitochondrial oxidative phosphorylation is the major contributor to cardiac energy production (95%) while cytosolic glycolysis has a marginal contribution (5%). The heart can dramatically and swiftly switch between energy-producing pathways and/or alter the share from each of the energy substrates based on cardiac workload, availability of each energy substrate and neuronal and hormonal activity. The heart is equipped with a highly sophisticated and powerful mitochondrial machinery which synchronizes cardiac energy production from different substrates and orchestrates the rate of ATP production to accommodate its contractility demands. This review discusses mitochondrial cardiac energy metabolism and how it is regulated. This includes a discussion on the allosteric control of cardiac energy metabolism by short-chain coenzyme A esters, including malonyl CoA and its effect on cardiac metabolic preference. We also discuss the transcriptional level of energy regulation and its role in the maturation of cardiac metabolism after birth and cardiac adaptability for different metabolic conditions and energy demands. The role post-translational modifications, namely phosphorylation, acetylation, malonylation, succinylation and glutarylation, play in regulating mitochondrial energy metabolism is also discussed.

scholarly journals The PPARα-PGC-1αAxis Controls Cardiac Energy Metabolism in Healthy and Diseased Myocardium

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Jennifer G. Duncan ◽  
Brian N. Finck
Keyword(s):  
Energy Metabolism ◽  
Transcriptional Control ◽  
Mitochondrial Energy Metabolism ◽  
Multiple Substrates ◽  
Energy Demands ◽  
Expression Of Genes ◽  
Cardiac Energy Metabolism ◽  
Genes Encoding ◽  
Mammalian Myocardium ◽  
Cardiac Energy

The mammalian myocardium is an omnivorous organ that relies on multiple substrates in order to fulfill its tremendous energy demands. Cardiac energy metabolism preference is regulated at several critical points, including at the level of gene transcription. Emerging evidence indicates that the nuclear receptor PPARαand its cardiac-enriched coactivator protein, PGC-1α, play important roles in the transcriptional control of myocardial energy metabolism. The PPARα-PGC-1αcomplex controls the expression of genes encoding enzymes involved in cardiac fatty acid and glucose metabolism as well as mitochondrial biogenesis. Also, evidence has emerged that the activity of the PPARα-PGC-1αcomplex is perturbed in several pathophysiologic conditions and that altered activity of this pathway may play a role in cardiomyopathic remodeling. In this review, we detail the current understanding of the effects of the PPARα-PGC-1αaxis in regulating mitochondrial energy metabolism and cardiac function in response to physiologic and pathophysiologic stimuli.

Effect of Ca2+ on cardiac mitochondrial energy production is modulated by Na+ and H+ dynamics

2007 ◽  
Vol 292 (6) ◽  
pp. C2004-C2020 ◽  
Author(s):  
My-Hanh T. Nguyen ◽  
S. J. Dudycha ◽  
M. Saleet Jafri
Keyword(s):  
Energy Metabolism ◽  
Energy Production ◽  
Hydrogen Exchange ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Calcium Dynamics ◽  
Mitochondrial Energy Metabolism ◽  
Acid Cycle ◽  
Atp Production ◽  
Sodium Hydrogen

The energy production of mitochondria in heart increases during exercise. Several works have suggested that calcium acts at multiple control points to activate net ATP production in what is termed “parallel activation”. To study this, a computational model of mitochondrial energy metabolism in the heart has been developed that integrates the Dudycha-Jafri model for the tricarboxylic acid cycle with the Magnus-Keizer model for mitochondrial energy metabolism and calcium dynamics. The model improves upon the previous formulation by including an updated formulation for calcium dynamics, and new descriptions of sodium, hydrogen, phosphate, and ATP balance. To this end, it incorporates new formulations for the calcium uniporter, sodium-calcium exchange, sodium-hydrogen exchange, the F1F0-ATPase, and potassium-hydrogen exchange. The model simulates a wide range of experimental data, including steady-state and simulated pacing protocols. The model suggests that calcium is a potent activator of net ATP production and that as pacing increases energy production due to calcium goes up almost linearly. Furthermore, it suggests that during an extramitochondrial calcium transient, calcium entry and extrusion cause a transient depolarization that serve to increase NADH production by the tricarboxylic acid cycle and NADH consumption by the respiration driven proton pumps. The model suggests that activation of the F1F0-ATPase by calcium is essential to increase ATP production. In mitochondria very close to the release sites, the depolarization is more severe causing a temporary loss of ATP production. However, due to the short duration of the depolarization the net ATP production is also increased.

scholarly journals Very-Low-Density Lipoprotein: Complex Particles in Cardiac Energy Metabolism

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
You-Guo Niu ◽  
Rhys D. Evans
Keyword(s):  
Fatty Acids ◽  
Energy Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Nonesterified Fatty Acids ◽  
Wide Range ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

The heart is a major consumer of energy and is able to utilise a wide range of substrates including lipids. Nonesterified fatty acids (NEFA) were thought to be a favoured carbon source, but their quantitative contribution is limited because of their relative histotoxicity. Circulating triacylglycerols (TAGs) in the form of chylomicrons (CMs) and very-low-density lipoprotein (VLDL) are an alternative source of fatty acids and are now believed to be important in cardiac metabolism. However, few studies on cardiac utilisation of VLDL have been performed and the role of VLDL in cardiac energy metabolism remains unclear. Hearts utilise VLDL to generate ATP, but the oxidation rate of VLDL-TAG is relatively low under physiological conditions; however, in certain pathological states switching of energy substrates occurs and VLDL may become a major energy source for hearts. We review research regarding myocardial utilisation of VLDL and suggest possible roles of VLDL in cardiac energy metabolism: metabolic regulator and extracardiac energy storage for hearts.

scholarly journals Disruption of Glycolysis, TCA Cycle, Respiratory Chain, Calcium and Iron Homeostasis in Doxorubicin Induced Cardiomyopathy-An In-silico Approach

2021 ◽  
Vol 12 (6) ◽  
pp. 8527-8542
Keyword(s):  
Energy Metabolism ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Krebs Cycle ◽  
Atp Depletion ◽  
Critical Function ◽  
Free Iron ◽  
Atp Production ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Doxorubicin is a well-known anthracycline antibiotic that is frequently used to treat a variety of malignancies. However, its clinical use is limited due to its adverse consequences, most notably cardiomyopathy. In the present work, we evaluated the molecular mechanisms behind the impairment of cardiac energetics in doxorubicin-induced cardiomyopathy. According to molecular docking, the interaction of doxorubicin with phosphofructokinase (PKF) and α-enolase is likely to negatively affect glycolysis. The interaction between doxorubicin with HMOX1 results in the accumulation of free iron. The free iron contributes to the heme-driven toxicity and the oxidizing environment that results in reactive oxygen species (ROS) production resulting from cell death. Additionally, the interaction of doxorubicin with HMOX1 impairs the availability of iron required for the Krebs cycle and ETC function. The interaction between doxorubicin and PINK1 results in a reduced membrane potential, which results in calcium accumulation. On the other hand, a lack of iron and calcium in the mitochondrial matrix results in ATP depletion, impairing the Krebs cycle activity. At the same time, the primary cause of doxorubicin-induced cardiomyopathy is cardiac energy metabolism. Thus, our work shows that doxorubicin impairs the activity of PFK, α-enolase, HMOX1, and PINK1, resulting in ATP production failure. As a result of changes in the heart energy metabolism, this ultimately leads to dilated cardiomyopathy caused by doxorubicin. Understanding the critical function of cardiac energy metabolism in doxorubicin-induced cardiomyopathy is critical for overcoming the obstacles that effectively limit the clinical effectiveness of this life-saving anti-cancer treatment.

scholarly journals 251 Oxidation of energy substrates in tissues of Largemouth bass (Micropterus salmoides)

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 68-69 ◽  
Author(s):  
Xinyu Li ◽  
Guoyao Wu
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Fatty Acids ◽  
Largemouth Bass ◽  
The Body ◽  
Human Consumption ◽  
Aquatic Animal ◽  
Bicarbonate Buffer ◽  
Energy Substrates ◽  
Atp Production

Abstract Because of growing interest in producing Largemouth bass (HMB) as a source of high-quality protein for human consumption worldwide, it is imperative to understand the metabolism of nutrients (including amino acids and carbohydrate) in this aquatic animal. The present study tested the hypothesis that amino acids are oxidized at a higher rate than carbohydrates (e.g., glucose) and fatty acids (e.g., palmitate) to provide ATP for tissues of LMB fed a 45%-crude protein diet. The liver, intestine, kidney, and skeletal muscle were isolated from juvenile LMB and incubated at 26 °C (the body temperature of LMB) for 2 h in 1 ml of oxygenated Krebs–Henseleit bicarbonate buffer (pH 7.4) containing a mixture of nutrients (2 mM glutamate, 2 mM glutamine, 2 mM aspartate, 2 mM alanine, 2 mM leucine, 5 mM glucose, and 2 mM palmitate). The rate of oxidation of each energy substrate was determined by using [U-14C]-labeled glutamate, glutamine, aspartate, alanine, leucine, glucose, or palmitate and collecting 14CO2 from each tracer. Results indicated that aspartate, glutamate and glutamine were extensively oxidized in all the four tissues and contributed to 67% of total ATP production. Glutamate contributed to more ATP than glutamine in the intestine, whereas similar amounts of ATP were produced from glutamate and glutamine in the liver, kidneys and skeletal muscle. In all the four tissues, rates of oxidation of alanine, leucine, palmitate and glucose were low and each of those nutrients contributed to < 10% of total ATP production. Together, the oxidation of aspartate, glutamate, glutamine, alanine plus leucine provided 82–85% of total ATP for the liver, intestine, kidney, and skeletal muscle. We conclude that amino acids, rather than glucose and long-chain fatty acids, are the primary energy substrates in the major tissues of Largemouth bass.

scholarly journals Effects of Lipid Overload on Heart in Metabolic Diseases

2021 ◽  
Vol 53 (12) ◽  
pp. 771-778
Author(s):  
An Yan ◽  
Guinan Xie ◽  
Xinya Ding ◽  
Yi Wang ◽  
Liping Guo
Keyword(s):  
Cardiovascular Disease ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Glucose Metabolism ◽  
Diabetic Cardiomyopathy ◽  
Metabolic Diseases ◽  
Metabolism Disorder ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
Energy Metabolism Disorder

AbstractMetabolic diseases are often associated with lipid and glucose metabolism abnormalities, which increase the risk of cardiovascular disease. Diabetic cardiomyopathy (DCM) is an important development of metabolic diseases and a major cause of death. Lipids are the main fuel for energy metabolism in the heart. The increase of circulating lipids affects the uptake and utilization of fatty acids and glucose in the heart, and also affects mitochondrial function. In this paper, the mechanism of lipid overload in metabolic diseases leading to cardiac energy metabolism disorder is discussed.

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