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Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 82209

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Prof. Dr. Cesare Indiveri

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Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende (CS), Italy
Interests: carnitine; cell metabolism; membrane transporters; bioenergetics
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Dr. Lara Console

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Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende (CS), Italy
Interests: carnitine transporters; exosomes; post-translational modifications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Carnitine is a natural molecule involved in several metabolic processes in virtually all living organisms. In humans, it plays a well-known role in cell bioenergetics, since it is part of the carnitine shuttle that allows fatty acids to enter the mitochondrial matrix for β-oxidation. Carnitine is also involved in other important functions: participating to peroxisomal fatty acid oxidation, regulating the CoA/acyl-CoA balance among the different cell compartments, shuttling acyl units for VLDL assembly in the endoplasmic reticulum, avoiding acetyl-CoA trapping in mitochondria during glucidic metabolism, helping the excretion of some drugs as carnitine derivatives. Nowadays, it is well established that humans possess a biosynthetic pathway for carnitine, which, however, is not able to supply the amount of carnitine necessary for body functions. Carnitine homeostasis results from synthesis, absorption, and excretion through urine. This equilibrium is influenced by renal reabsorption which can partially compensate for insufficient dietary intake. Altered carnitine homeostasis, due to inherited defects of intestinal absorption, renal reabsorption, biosynthesis, or mitochondrial shuttling, lead to pathologies called carnitine deficiencies, with a variable degree of severity. Derangement of carnitine homeostasis seems to be involved also in other human diseases such as cancer, diabetes, inflammatory diseases, Autism Spectrum Disorders. Carnitine is used in human therapy since some of the inherited defects mentioned above can be partially rescued by high-dose carnitine administration; in addition, carnitine ad acetyl-carnitine seem to provide some benefits in neurological pathologies.

Last, but not least, carnitine plays important roles in the metabolism of microorganisms and plants.

In bacteria, carnitine can protect or enhance tolerance against several environmental insults such as salt, temperature, or pressure stress. Moreover, carnitine can be a carbon, nitrogen, and energy source. As in humans, also in yeast carnitine is involved in energy metabolism for the completion of the β-oxidation pathway. In plants, this molecule seems to be involved in the export of fatty acids from plastids, import of fatty acids into the ER, synthesis of specific glycerolipids, and cellular defense through its antioxidant and osmolyte properties. The role of carnitine in the oxidation of fatty acids in plants is less clear.

This Special Issue will collect the most recent findings on carnitine, with the purpose of providing a comprehensive and updated overview of this interesting molecule. We welcome submissions of original research papers and reviews from different disciplines including biochemistry and molecular biology, cell biology, genetics, nutrition, medical sciences, plant science, and microbiology.

Prof. Cesare Indiveri
Dr. Lara Console
Guest Editors

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Keywords

Carnitine
Acetyl-carnitine
Acyl-carnitine
Metabolism
Cell energetics
Membrane transport
Enzyme activity
Cell protection
Plant physiology
Oxidative stress
Osmotic stress
Fatty acid trafficking
Environmental stress
Human pathology
Gene expression

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Published Papers (10 papers)

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13 pages, 1731 KiB

Open AccessArticle

Effect of Copper on the Mitochondrial Carnitine/Acylcarnitine Carrier Via Interaction with Cys136 and Cys155. Possible Implications in Pathophysiology

by Nicola Giangregorio, Annamaria Tonazzi, Lara Console, Mario Prejanò, Tiziana Marino, Nino Russo and Cesare Indiveri

Molecules 2020, 25(4), 820; https://doi.org/10.3390/molecules25040820 - 13 Feb 2020

Cited by 9 | Viewed by 2557

Abstract

The effect of copper on the mitochondrial carnitine/acylcarnitine carrier (CAC) was studied. Transport function was assayed as [³H]carnitine/carnitine antiport in proteoliposomes reconstituted with the native protein extracted from rat liver mitochondria or with the recombinant CAC over-expressed in E. coli. Cu²⁺ (as well as Cu⁺) strongly inhibited the native transporter. The inhibition was reversed by GSH (reduced glutathione) or by DTE (dithioerythritol). Dose-response analysis of the inhibition of the native protein was performed from which an IC₅₀ of 1.6 µM for Cu²⁺ was derived. The mechanism of inhibition was studied by using the recombinant WT or Cys site-directed mutants of CAC. From the dose-response curve of the effect of Cu²⁺ on the recombinant protein, an IC₅₀ of 0.28 µM was derived. Inhibition kinetics revealed a non-competitive type of inhibition by Cu²⁺. However, a substrate protection experiment indicated that the interaction of Cu²⁺ with the protein occurred in the vicinity of the substrate-binding site. Dose-response analysis on Cys mutants led to much higher IC₅₀ values for the mutants C136S or C155S. The highest value was obtained for the C136/155S double mutant, indicating the involvement of both Cys residues in the interaction with Cu²⁺. Computational analysis performed on the WT CAC and on Cys mutants showed a pattern of the binding energy mostly overlapping the binding affinity derived from the dose-response analysis. All the data concur with bridging of Cu²⁺ with the two Cys residues, which blocks the conformational changes required for transport cycle. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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18 pages, 20162 KiB

Open AccessArticle

L-Carnitine Is Involved in Hyperbaric Oxygen-Mediated Therapeutic Effects in High Fat Diet-Induced Lipid Metabolism Dysfunction

by Junhua Yuan, Qixiao Jiang, Limin Song, Yuan Liu, Manwen Li, Qian Lin, Yanrun Li, Kaizhen Su, Zhengye Ma, Yifei Wang, Defeng Liu and Jing Dong

Molecules 2020, 25(1), 176; https://doi.org/10.3390/molecules25010176 - 1 Jan 2020

Cited by 7 | Viewed by 4947

Abstract

Lipid metabolism dysfunction and obesity are serious health issues to human beings. The current study investigated the effects of hyperbaric oxygen (HBO) against high fat diet (HFD)-induced lipid metabolism dysfunction and the roles of L-carnitine. C57/B6 mice were fed with HFD or normal chew diet, with or without HBO treatment. Histopathological methods were used to assess the adipose tissues, serum free fatty acid (FFA) levels were assessed with enzymatic methods, and the endogenous circulation and skeletal muscle L-carnitine levels were assessed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, western blotting was used to assess the expression levels of PPARα, CPT1b, pHSL/HSL, and UCP1. HFD treatment increased body/adipose tissue weight, serum FFA levels, circulation L-carnitines and decreased skeletal muscle L-carnitine levels, while HBO treatment alleviated such changes. Moreover, HFD treatment increased fatty acid deposition in adipose tissues and decreased the expression of HSL, while HBO treatment alleviated such changes. Additionally, HFD treatment decreased the expression levels of PPARα and increased those of CPT1b in skeletal muscle, while HBO treatment effectively reverted such changes as well. In brown adipose tissues, HFD increased the expression of UCP1 and the phosphorylation of HSL, which was abolished by HBO treatment as well. In summary, HBO treatment may alleviate HFD-induced fatty acid metabolism dysfunction in C57/B6 mice, which seems to be associated with circulation and skeletal muscle L-carnitine levels and PPARα expression. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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14 pages, 2012 KiB

Open AccessFeature PaperReview

Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Conceptual Approach

by Pushpa Raj Joshi and Stephan Zierz

Molecules 2020, 25(8), 1784; https://doi.org/10.3390/molecules25081784 - 13 Apr 2020

Cited by 40 | Viewed by 11277

Abstract

Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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14 pages, 590 KiB

Open AccessReview

Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise?

by Antonio Gnoni, Serena Longo, Gabriele V. Gnoni and Anna M. Giudetti

Molecules 2020, 25(1), 182; https://doi.org/10.3390/molecules25010182 - 1 Jan 2020

Cited by 77 | Viewed by 22266

Abstract

l-Carnitine is an amino acid derivative widely known for its involvement in the transport of long-chain fatty acids into the mitochondrial matrix, where fatty acid oxidation occurs. Moreover, l-Carnitine protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Circulating carnitine is mainly supplied by animal-based food products and to a lesser extent by endogenous biosynthesis in the liver and kidney. Human muscle contains high amounts of carnitine but it depends on the uptake of this compound from the bloodstream, due to muscle inability to synthesize carnitine. Mitochondrial fatty acid oxidation represents an important energy source for muscle metabolism particularly during physical exercise. However, especially during high-intensity exercise, this process seems to be limited by the mitochondrial availability of free l-carnitine. Hence, fatty acid oxidation rapidly declines, increasing exercise intensity from moderate to high. Considering the important role of fatty acids in muscle bioenergetics, and the limiting effect of free carnitine in fatty acid oxidation during endurance exercise, l-carnitine supplementation has been hypothesized to improve exercise performance. So far, the question of the role of l-carnitine supplementation on muscle performance has not definitively been clarified. Differences in exercise intensity, training or conditioning of the subjects, amount of l-carnitine administered, route and timing of administration relative to the exercise led to different experimental results. In this review, we will describe the role of l-carnitine in muscle energetics and the main causes that led to conflicting data on the use of l-carnitine as a supplement. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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23 pages, 2825 KiB

Open AccessReview

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

by Barbara Juraszek and Katarzyna A. Nałęcz

Molecules 2020, 25(1), 14; https://doi.org/10.3390/molecules25010014 - 19 Dec 2019

Cited by 38 | Viewed by 8122

Abstract

Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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10 pages, 235 KiB

Open AccessReview

Effects of l-Carnitine in Patients with Autism Spectrum Disorders: Review of Clinical Studies

by Michele Malaguarnera and Omar Cauli

Molecules 2019, 24(23), 4262; https://doi.org/10.3390/molecules24234262 - 22 Nov 2019

Cited by 21 | Viewed by 5931

Abstract

Carnitine is an amino acid derivative, which plays several important roles in human physiology, in the central nervous system, and for mitochondrial metabolism, in particular. Altered carnitine metabolic routes have been associated with a subgroup of patients with autism spectrum disorders (ASD) and could add to the pathophysiology associated with these disorders. We review the current evidence about the clinical effects of carnitine administration in ASD in both non-syndromic forms and ASD associated with genetic disorders. Two randomized clinical trials and one open-label prospective trial suggest that carnitine administration could be useful for treating symptoms in non-syndromic ASD. The effect of carnitine administration in ASD associated with genetic disorders is not conclusive because of a lack of clinical trials and objectives in ASD evaluation, but beneficial effects have also been reported for other comorbid disorders, such as intellectual disability and muscular strength. Side effects observed with a dose of 200 mg/kg/day consisted of gastro-intestinal symptoms and a strong, heavy skin odor. Doses of about 50–100 mg/kg/day are generally well tolerated. Further clinical trials with the identification of the subgroup of ASD patients that would benefit from carnitine administration are warranted. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

12 pages, 214 KiB

Open AccessReview

Current Opinion on Usage of L-Carnitine in End-Stage Renal Disease Patients on Peritoneal Dialysis

by Mario Bonomini, Lorenzo Di Liberato, Victor Zammit and Arduino Arduini

Molecules 2019, 24(19), 3449; https://doi.org/10.3390/molecules24193449 - 23 Sep 2019

Cited by 20 | Viewed by 3826

Abstract

The advantages of peritoneal dialysis (PD) over hemodialysis (HD) are well-documented. Notwithstanding, only a small proportion of patients with end-stage renal disease (ESRD) are managed with PD. This may be related to the high glucose load that PD solutions in current use have on the patient. The effects of such excess glucose include the relatively early limitation of the ultrafiltration capacity of the peritoneal membrane, and the metabolic effects associated with hyperglycemia, e.g., decreased insulin sensitivity. This article describes the advantages that may be realized by the glucose-sparing effects of substituting part of the glucose load with other osmotically active metabolites, particularly L-carnitine. The latter is anticipated to have metabolic advantages of its own, especially as in PD patients, high plasma concentrations can be achieved in the absence of renal clearance. Besides its better biocompatibility, L-carnitine demonstrates anti-anemia action due to its effects on erythropoiesis, and positive effects on the longevity and deformability of erythrocytes. Observations from our trials on the use of carnitine-enriched PD solutions have demonstrated the effectiveness of L-carnitine as an efficient osmolyte in PD, and its favorable effect on the insulin sensitivity of the patients. The significance of these findings for future developments in the use of PD in the management of patients with ESRD is discussed. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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16 pages, 485 KiB

Open AccessReview

Carnitine Inborn Errors of Metabolism

by Mohammed Almannai, Majid Alfadhel and Ayman W. El-Hattab

Molecules 2019, 24(18), 3251; https://doi.org/10.3390/molecules24183251 - 6 Sep 2019

Cited by 86 | Viewed by 9906

Abstract

Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine–acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine–acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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19 pages, 884 KiB

Open AccessPerspective

The Nutraceutical Value of Carnitine and Its Use in Dietary Supplements

by Alessandra Durazzo, Massimo Lucarini, Amirhossein Nazhand, Selma B. Souto, Amélia M. Silva, Patrícia Severino, Eliana B. Souto and Antonello Santini

Molecules 2020, 25(9), 2127; https://doi.org/10.3390/molecules25092127 - 1 May 2020

Cited by 25 | Viewed by 9648

Abstract

Carnitine can be considered a conditionally essential nutrient for its importance in human physiology. This paper provides an updated picture of the main features of carnitine outlining its interest and possible use. Particular attention has been addressed to its beneficial properties, exploiting carnitine’s properties and possible use by considering the main in vitro, in animal, and human studies. Moreover, the main aspects of carnitine-based dietary supplements have been indicated and defined with reference to their possible beneficial health properties. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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8 pages, 779 KiB

Open AccessBrief Report

Effects of Exercise Training on Renal Carnitine Biosynthesis and Uptake in the High-Fat and High-Sugar-Fed Mouse

by Aman Upadhyay, Layla Al-Nakkash and Tom L. Broderick

Molecules 2020, 25(9), 2100; https://doi.org/10.3390/molecules25092100 - 30 Apr 2020

Cited by 2 | Viewed by 2357

Abstract

(1) Background: Diet-induced obesity inhibits hepatic carnitine biosynthesis. Herein, the effects of high-fat (HF) and high-sugar (HFHS) feeding and exercise training (ET) on renal carnitine biosynthesis and uptake were determined. (2) Methods: Male C57BL/6J mice were assigned to the following groups: lean control (standard chow), HFHS diet, and HFHS diet with ET. ET consisted of 150 min of treadmill running per week for 12 weeks. Protein levels of γ-butyrobetaine hydroxylase (γ-BBH) and organic cation transporter-2 (OCTN2) were measured as markers of biosynthesis and uptake, respectively. (3) Results: HFHS feeding induced an obese diabetic state with accompanying hypocarnitinemia, reflected by decreased free carnitine levels in plasma and kidney. This hypocarnitinemia was associated with decreased γ-BBH (~30%) and increased OCTN2 levels (~50%). ET failed to improve the obesity and hyperglycemia, but improved insulin levels and prevented the hypocarnitinemia. ET increased protein levels of γ-BBH, whereas levels of OCTN2 were decreased. Peroxisome proliferator-activated receptor-alpha content was not changed by the HFHS diet or ET. (4) Conclusions: Our results indicate that ET prevents the hypocarnitinemia induced by HFHS feeding by increasing carnitine biosynthesis in kidney. Increased expression of OCTN2 with HFHS feeding suggests that renal uptake was stimulated to prevent carnitine loss. Full article

(This article belongs to the Special Issue Carnitine: An Interesting Molecule in Metabolism, Pathophysiology and Nutrition)

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