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![Metabolic pathways for major substrates in the body. Adapted from Virmani et al., 2015 [2]. The body utilizes carbohydrates as glucose, lipids as free fatty acids and proteins as amino acids as the major substrates for the production of ATP energy. Much of the energy from these substrates is produced in the mitochondria.](publication/358930749/figure/fig1/AS:1133111513485312@1647166245229/Metabolic-pathways-for-major-substrates-in-the-body-Adapted-from-Virmani-et-al-2015.png)
Metabolic pathways for major substrates in the body. Adapted from Virmani et al., 2015 [2]. The body utilizes carbohydrates as glucose, lipids as free fatty acids and proteins as amino acids as the major substrates for the production of ATP energy. Much of the energy from these substrates is produced in the mitochondria.
Source publication
Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resist...
Contexts in source publication
Context 1
... of the cellular energy production comes from mitochondria whose main function is the production of adenosine triphosphate (ATP), which is needed to drive cellular processes (Figure 1). ...
Context 2
... of the cellular energy production comes from mitochondria whose main function is the production of adenosine triphosphate (ATP), which is needed to drive cellular processes (Figure 1). ...
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... is the only molecule capable of carrying fatty acids across the inner membrane and into the mitochondria, where they undergo β-oxidation. There is a complex system of enzymes and transporters that permit the L-carnitine molecule to enter the cell and to transfer fatty acid molecules into the mitochondria (Figures 1 and 2). ...
Context 4
... is the only molecule capable of carrying fatty acids across the inner membrane and into the mitochondria, where they undergo β -oxidation. There is a complex system of enzymes and transporters that permit the L-carnitine molecule to enter the cell and to transfer fatty acid molecules into the mitochondria (Figures 1 and 2). ...
Citations
... Metabolic compounds such as L-carnitine have been used as dietary supplements alone or in combination to aid metabolic disorders. L-carnitine is the only molecule capable of transporting long-chain fatty acids across the inner mitochondrial membrane, where they are metabolized into short-chain fats, as β-oxidation cleaves two carbons per cycle to form a single acetyl-CoA molecule that can enter the citric acid cycle to produce ATP 55,56 . Acylcarnitines are the esters formed when fatty acids bind to L-carnitine to be carried into the mitochondria; thus, analysis of acylcarnitine species are indicative of fat uptake and metabolism in the mitochondria 55,56 . ...
... L-carnitine is the only molecule capable of transporting long-chain fatty acids across the inner mitochondrial membrane, where they are metabolized into short-chain fats, as β-oxidation cleaves two carbons per cycle to form a single acetyl-CoA molecule that can enter the citric acid cycle to produce ATP 55,56 . Acylcarnitines are the esters formed when fatty acids bind to L-carnitine to be carried into the mitochondria; thus, analysis of acylcarnitine species are indicative of fat uptake and metabolism in the mitochondria 55,56 . Obese mares provided the complex diet supplement (OBD) resulted in increased circulating free L-carnitine and total acetylcarnitine species with a larger proportion of short-chain than medium-or long-chain acylcarnitines, implying completeness of β-oxidation due to improved mitochondrial function and fatty acid metabolism 56 . ...
... Acylcarnitines are the esters formed when fatty acids bind to L-carnitine to be carried into the mitochondria; thus, analysis of acylcarnitine species are indicative of fat uptake and metabolism in the mitochondria 55,56 . Obese mares provided the complex diet supplement (OBD) resulted in increased circulating free L-carnitine and total acetylcarnitine species with a larger proportion of short-chain than medium-or long-chain acylcarnitines, implying completeness of β-oxidation due to improved mitochondrial function and fatty acid metabolism 56 . We subsequently examined the isolated effect of dietary L-carnitine on insulin dysregulation and lipid metabolism www.nature.com/scientificreports/ in obese mares (OBLC). ...
Obesity is a complex disease associated with augmented risk of metabolic disorder development and cellular dysfunction in various species. The goal of the present study was to investigate the impacts of obesity on the metabolic health of old mares as well as test the ability of diet supplementation with either a complex blend of nutrients designed to improve equine metabolism and gastrointestinal health or L-carnitine alone to mitigate negative effects of obesity. Mares (n = 19, 17.9 ± 3.7 years) were placed into one of three group: normal-weight (NW, n = 6), obese (OB, n = 7) or obese fed a complex diet supplement for 12 weeks (OBD, n = 6). After 12 weeks and completion of sample collections, OB mares received L-carnitine alone for an additional 6 weeks. Obesity in mares was significantly associated with insulin dysregulation, reduced muscle mitochondrial function, and decreased skeletal muscle oxidative capacity with greater ROS production when compared to NW. Obese mares fed the complex diet supplement had better insulin sensivity, greater cell lipid metabolism, and higher muscle oxidative capacity with reduced ROS production than OB. L-carnitine supplementation alone did not significantly alter insulin signaling, but improved lipid metabolism and muscle oxidative capacity with reduced ROS. In conclusion, obesity is associated with insulin dysregulation and altered skeletal muscle metabolism in older mares. However, dietary interventions are an effective strategy to improve metabolic status and skeletal muscle mitochondrial function in older mares.
... Rabbits, owing to their anatomical and physiological similarities to humans, are often utilized as experimental models for situdying the effects of natural products on organ systems (11). The hepatic and renal systems play crucial roles in maintaining homeostasis within the body, and any disturbance in their functions could have significant health implications (12). The impact of Carica papaya on these vital organs is essential for establishing its safety profile and providing evidence-based recommendations for its use in traditional and complementary medicine (10). ...
Objective: To assess the impact of Carica papaya leaves and seeds on hepatic and renal function in a controlled rabbit model. Methodology: In a 45-day experimental study at Baqai Medical University, Karachi, 18 healthy adult rabbits were allocated into five groups. All groups received varying doses of papaya seed or leaf extracts. Liver and renal function assessments were performed at 15-day intervals, providing insights into the impact of Carica papaya extracts on these vital physiological functions. Results: The administration of papaya extracts demonstrated a generally favorable safety profile, with no disruption to liver enzymes and renal biochemistries. However, the group receiving papaya seed extract at 500mg exhibited a noteworthy increase in albumin levels. While this may suggest a potential risk of dehydration, it did not impact liver synthetic function. Notably, renal function remained within clinically acceptable ranges across all groups, emphasizing the overall safety of the papaya extracts. Conclusion: The findings suggest that Carica papaya extract, particularly from leaves, holds therapeutic potential for promoting liver and kidney health. Importantly, the observed effects were without significant adverse consequences. These results provide valuable insights into the safety and potential benefits of Carica papaya extracts, laying the foundation for further research and exploration of their applications in supporting hepatic and renal functions.
... In the context of PD, comprehensive analyses have revealed significant decreases in long-chain acylcarnitines, suggesting an initial suppression of mitochondrial β-oxidation and identifying these metabolites as promising diagnostic biomarkers [47]. Similarly, mitochondrial dysfunction, characterized by the inability to maintain metabolic flexibility and energy production, is a common pathway in neurodegenerative diseases, with L-carnitine playing a pivotal role in supporting mitochondrial function through fatty acid oxidation and in mitigating oxidative stress and neurotoxicity [48]. This is further supported by studies on AD, where amyloid beta-peptides cause neuronal injury through excitotoxic mechanisms, with L-carnitine and its derivatives offering neuroprotective effects by enhancing mitochondrial function, reducing oxidative stress, and improving neuronal viability [49][50][51]. ...
Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.
... Consequently, it is important to recognize physical inactivity as an essential determinant in the context of weight gain and onset of obesity. 2 L-carnitine is an amino acid-like compound that plays a role in energy metabolism by supporting transport of fatty acids into the mitochondria, where they can be used for energy production through β-oxidation. 3 L-carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. 4 Therefore, without carnitine most of the dietary lipids cannot be used as an energy source and our body would accumulate fatty acids promoting obesity. ...
Background Despite extensive research, the effects of L-carnitine supplementation in treating obesity are still unclear and equivocal. L-carnitine transports fatty acids into mitochondria for oxidation and is marketed as a weight loss supplement. The purpose of the present research is to investigate the efficacy of L-carnitine during concurrent training on the functional capacities and body composition in obese men.
Methods Thirty nonactive, obese males (age = 37.2 ± 1.5 years; body mass index = 33.8 ± 2.5 kg/m2) participated in this research. The participants were randomly divided into three groups: experimental group 1 (EXP1)—concurrent training with L-carnitine supplementation; experimental group 2 (EXP2)—L-carnitine supplementation without training; and control group—without training or L-carnitine supplementation. Concurrent training was performed for 8 weeks, three sessions per week, with a training intensity ranging from 60 to 75% of the maximum heart rate reserve and one-repetition maximum. Both experimental groups were supplemented with 35 mg L-carnitine supplement per kilogram body weight. Various functional and body composition variables were collected at three time points (pre-test, mid-test, and post-test).
Results A number of variables were significantly improved in EXP1 after 4 and 8 weeks (systolic blood pressure, maximal oxygen consumption, weight, body mass index, and one-repetition maximum) and only after 8-weeks (diastolic blood pressure, resting heart rate, percentage of body fat, and fat-free mass). No significant changes were observed for EXP2 and the control group.
Conclusion L-carnitine supplementation, in conjunction with concurrent training, emerges as a highly effective approach for enhancing body composition and boosting functional capacities in obese adult men. Therefore, it is recommended that overweight male individuals integrate concurrent training into their regimen while taking L-carnitine.
... Given the need for excessive energy production from fatty acids, this result is not surprising, since carnitine and its acetylcarnitines have a central role in the transport of fatty acids in the mitochondrion and in β-oxidation. Fatty acyl-CoA production is mediated by the following four main enzymes: fatty acyl-CoA synthetase (FACS), carnitine palmitoyl transferase 1 (CPT1), carnitine acylcarnitine translocase (CACT), and carnitine palmitoyl transferase 2 (CPT2) [49]. Inhibitors of CPT1 have already shown in vitro efficacy in reducing proliferation of chronic lymphocytic leukemia cells [50]. ...
Introduction: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy. Despite high cure rates, several questions remain regarding predisposition, response to treatment, and prognosis of the disease. The role of intermediary metabolism in the individualized mechanistic pathways of the disease is unclear. We have hypothesized that children with any (sub)type of ALL have a distinct metabolomic fingerprint at diagnosis when compared: (i) to a control group; (ii) to children with a different (sub)type of ALL; (iii) to the end of the induction treatment. Materials and Methods: In this prospective case–control study (NCT03035344), plasma and urinary metabolites were analyzed in 34 children with ALL before the beginning (D0) and at the end of the induction treatment (D33). Their metabolic fingerprint was defined by targeted analysis of 106 metabolites and compared to that of an equal number of matched controls. Multivariate and univariate statistical analyses were performed using SIMCAP and scripts under the R programming language. Results: Metabolomic analysis showed distinct changes in patients with ALL compared to controls on both D0 and D33. The metabolomic fingerprint within the patient group differed significantly between common B-ALL and pre-B ALL and between D0 and D33, reflecting the effect of treatment. We have further identified the major components of this metabolic dysregulation, indicating shifts in fatty acid synthesis, transfer and oxidation, in amino acid and glycerophospholipid metabolism, and in the glutaminolysis/TCA cycle. Conclusions: The disease type and time point-specific metabolic alterations observed in pediatric ALL are of particular interest as they may offer potential for the discovery of new prognostic biomarkers and therapeutic targets.
... Carnitine metabolism is also shown to be altered at lines n. 15, 30, 38, 67, 78 and 81 in Table 1. Carnitines metabolism is mostly at the mitochondrial level and is crucial for the fatty acid oxidation and energy production [48][49][50][51], and carnitines are reported as key mitochondrial players in different pathologic conditions [50,[52][53][54][55][56]. The potential role carnitine-metabolism-related genes may play in melanoma growth was then confirmed by the analysis depicted in Table 2 and Figure 9, indicating significant expression change and significant correlation with survival in melanoma patients. ...
... Polyamine, putrescin and asparagine metabolism are known to be strongly altered in cancer [59][60][61]. Metabolism of amino acids, polyamines, ornithine and taurine are all strongly inter-connected, and their expression was in fact found significantly altered in Table 1 (see lines n. 6,8,18,19,20,23,35,39,41,42,52,54,59 and 79) indicating a profound metabolism alteration of all amino acids and proteins. Finally, choline-related metabolism was found modified in Table 1 (see line n. ...
Miconazole is an antimycotic drug showing anti-cancer effects in several cancers. However, little is known on its effects in melanoma. A375 and SK-MEL-28 human melanoma cell lines were exposed to miconazole and clotrimazole (up to 100 mM). Proliferation, viability with MTT assay and vascular mimicry were assayed at 24 h treatment. Molecular effects were measured at 6 h, namely, ATP-, ROS-release and mitochondria-related cytofluorescence. A metabolomic profile was also investigated at 6 h treatment. Carnitine was one of the most affected metabolites; therefore, the expression of 29 genes involved in carnitine metabolism was investigated in the public platform GEPIA2 on 461 melanoma patients and 558 controls. After 24 h treatments, miconazole and clotrimazole strongly and significantly inhibited proliferation in the presence of 10% serum on either melanoma cell lines; they also strongly reduced viability and vascular mimicry. After 6 h treatment, ATP reduction and ROS increase were observed, as well as a significant reduction in mitochondria-related fluorescence. Further, in A375, miconazole strongly and significantly altered expression of several metabolites including carnitines, phosphatidyl-cholines, all amino acids and several other small molecules, mostly metabolized in mitochondria. The expression of 12 genes involved in carnitine metabolism was found significantly modified in melanoma patients, 6 showing a significant impact on patients’ survival. Finally, miconazole antiproliferation activity on A375 was found completely abrogated in the presence of carnitine, supporting a specific role of carnitine in melanoma protection toward miconazole effect, and was significantly reversed in the presence of caspases inhibitors such as ZVAD-FMK and Ac-DEVD-CHO, and a clear pro-apoptotic effect was observed in miconazole-treated cells, by FACS analysis of Annexin V-FITC stained cells. Miconazole strongly affects proliferation and other biological features in two human melanoma cell lines, as well as mitochondria-related functions such as ATP- and ROS-release, and the expression of several metabolites is largely dependent on mitochondria function. Miconazole, likely acting via carnitine and mitochondria-dependent apoptosis, is therefore suggested as a candidate for further investigations in melanoma treatments.
... L-carnitine, an essential compound, plays vital roles in the body, particularly in energy metabolism [1][2][3]. Carnitine accumulates in skeletal muscle [4], and its primary role is to transport fatty acids (FAs) to the mitochondria, thereby contributing to the skeletal muscle energy supply [5,6]. Also, in cardiac muscle, the primary energy source of the human heart is free FAs, which are broken down by β-oxidation and enter the tricarboxylic acid (TCA) cycle, where they ultimately convert into adenosine triphosphate (ATP). ...
Introduction
L-carnitine exerts protective effects, such as maintaining mitochondrial functions and decreasing reactive oxygen species, while acylcarnitine (AC) is linked to the development of heart failure and atherosclerosis.
Hypothesis
Serum carnitines play important pathophysiological roles in cardiovascular diseases.
Methods
Pre-operative biochemical data were obtained from 117 patients (71 men, average age 69.9 years) who underwent surgery for cardiovascular diseases. Measurements included pre-operative biochemical data including estimated glomerular filtration rate (eGFR), physical functions, skeletal muscle mass index (SMI) measured by bioelectrical impedance analysis, anterior thigh muscle thickness (MTh) measured by ultrasound, and routine echocardiography. Carnitine components were measured with the enzyme cycling method. Muscle wasting was diagnosed based on the Asian Working Group for Sarcopenia criteria.
Results
Plasma brain natriuretic peptide (BNP) level was correlated with serum free carnitine (FC) and AC level, and the acylcarnitine/free carnitine ratio (AC/FC). AC/FC was elevated with stage of chronic kidney disease. In multivariate analysis, log (eGFR) and log (BNP) were extracted as independent factors to define log (serum AC) (eGFR: β = 0.258, p = 0.008; BNP: β = 0.273, p = 0.011), even if corrected for age, sex and body mass index. AC/FC was negatively correlated with hand-grip strength (r = -0.387, p = 0.006), SMI (r = -0.314, p = 0.012), and anterior thigh MTh (r = -0.340, p = 0.014) in men.
Conclusions
A significant association between serum AC level and AC/FC, and chronic kidney disease and heart failure exists in patients with cardiovascular diseases who have undergone cardiovascular surgery. Skeletal muscle loss and muscle wasting are also linked to the elevation of serum AC level and AC/FC.
... This effect may be attributed to the fact that, as an effective antioxidant, L-carnitine can prevent the generation of reactive oxygen species (ROS) and promote their elimination, thereby safeguarding sperm from oxidative damage (22). In addition, Lcarnitine functions as a mitochondrial protective agent by regulating the acetyl-CoA/CoA ratio and preventing ROSmediated cell apoptosis, among other functions (23). However, optimal sperm function and fertilization require moderate levels of oxidative stress, but excessive oxidative stress can result in sperm damage and infertility (24). ...
Background
L-carnitine therapy for idiopathic sperm abnormalities exhibits variable effectiveness, and currently, there are no established criteria to predict patient response. This study investigated correlations between seminal plasma markers and semen parameters to identify biomarkers that can guide indications for L-carnitine therapy indications in patients with idiopathic sperm abnormalities.
Methods
A retrospective review was conducted on 223 male patients with idiopathic oligoasthenoteratospermia, who sought medical attention at our clinic between January 2020 and October 2022. These patients underwent a pretreatment seminal plasma biochemical analysis, followed by a three-month continuous L-carnitine treatment. The correlation between seminal plasma biochemical parameters and pretreatment semen parameters was analyzed. Semen quality was compared between cases with normal and abnormal seminal plasma biochemical parameters, both pretreatment and posttreatment. The correlation between the changes in semen parameters after treatment and seminal plasma biochemical parameters were investigated.
Results
Correlation analyses revealed significant associations between all pretreatment semen parameters and seminal plasma biochemical markers, except for liquefying time and the ratio of normal morphology. Subgroup analysis, stratified by seminal fructose, zinc, citric acid, and neutral glycosidase levels, demonstrated that abnormal groups exhibited significantly different levels of semen parameters compared with the normal groups. The changing difference and changing ratio in the ratio of forward motile sperm showed a negative correlation with seminal fructose levels (r=-0.165 and -0.144). The changing difference in semen volume was negatively correlated with the level of seminal neutral glycosidase (r=-0.158). The changing ratio in semen volume, sperm concentration, total sperm count, and count of forward motile sperm all exhibited negative correlations with the levels of seminal neutral glycosidase (range from -0.178 to -0.224).
Conclusion
Seminal plasma biochemical markers, particularly fructose and neutral glycosidase, may serve as valuable indicators for determining the eligibility of patients with idiopathic sperm abnormalities for L-carnitine therapy.
... This process aids delivery of longchain FAs across the inner mitochondrial membrane during β-oxidation of FAs. 72 The effects of several acylcarnitine species on GDM vary depending on chain length, and medium-chain acylcarnitine may induce pancreatic β-cell dysfunction. 73,74 By regulating phosphorylation of mTOR, acylcarnitine dysfunction can interfere with insulin signaling and result in IR. 38 The urine metabolic fingerprint of GDM in Dudzik's study demonstrated not only changes in amino acids but also abnormalities in carnitine metabolism. ...
Gestational diabetes mellitus (GDM) is one of the most common metabolic complications during pregnancy, threatening both maternal and fetal health. Prediction and diagnosis of GDM is not unified. Finding effective biomarkers for GDM is particularly important for achieving early prediction, accurate diagnosis and timely intervention. Urine, due to its accessibility in large quantities, noninvasive collection and easy preparation, has become a good sample for biomarker identification. In recent years, a number of studies using metabolomics and proteomics approaches have identified differential expressed urine metabolites and proteins in GDM patients. In this review, we summarized these potential urine biomarkers for GDM prediction and diagnosis and elucidated their role in development of GDM.
... Though certain details of the underlying biological mechanisms of insulin resistance (IR) and T2DM remain unclear, hyperglycemia is known to be associated with mitochondrial dysfunction (14)(15)(16). In the cytosol, L-carnitine receives acyl groups from acyl-CoA, and the acylcarnitines are (17,18). In mitochondria, acylcarnitines donate the acyl groups to free CoA to serve as substrates for oxidative metabolism, and L-carnitine is then exported out of mitochondria (17). ...
Diabetic peripheral neuropathy (DPN) is a highly prevalent chronic complication in type 2 diabetes (T2D) for which no effective treatment is available. In this multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial in China, patients with T2D with DPN received acetyllevocarnitine hydrochloride (ALC; 1,500 mg/day; n = 231) or placebo (n = 227) for 24 weeks, during which antidiabetic therapy was maintained. A significantly greater reduction in modified Toronto clinical neuropathy score (mTCNS) as the primary end point occurred in the ALC group (−6.9 ± 5.3 points) compared with the placebo group (−4.7 ± 5.2 points; P < 0.001). Effect sizes (ALC 1.31 and placebo 0.85) represented a 0.65-fold improvement in ALC treatment efficacy. The mTCNS values for pain did not differ significantly between the two groups (P = 0.066), whereas the remaining 10 components of mTCNS showed significant improvement in the ALC group compared with the placebo group (P < 0.05 for all). Overall results of electrophysiological measurements were inconclusive, with significant improvement in individual measurements limited primarily to the ulnar and median nerves. Incidence of treatment-emergent adverse events was 51.2% in the ALC group, among which urinary tract infection (5.9%) and hyperlipidemia (7.9%) were most frequent.
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