L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine

McCann, Marc R.; Rosa, Mery Vet George De la; Rosania, Gus R.; Stringer, Kathleen A.

doi:10.3390/metabo11010051

Cited by 190 publications

(180 citation statements)

References 135 publications

(210 reference statements)

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“…Since circulating C16:1 9cis has been shown to be proportional to FM [ 48 ], the negative correlation between CRF and C16:1 9cis might be explained by the generally lower FM (%) in fitter females. Acylcarnitines are intermediates in the transport of LCFAs to mitochondria or byproducts of β-oxidation [ 49 ]. Although blood acylcarnitines have been identified as markers of insulin resistance, mitochondrial overload, and incomplete fat oxidation [ 50 ], they are also physiologically elevated in conditions with high lipolytic rates [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Relationship between the Cardiorespiratory Fitness and Plasma Metabolite Patterns in Healthy Humans—Results of the KarMeN Study

et al. 2021

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Cardiorespiratory fitness (CRF) represents a strong predictor of all-cause mortality and is strongly influenced by regular physical activity (PA). However, the biological mechanisms involved in the body’s adaptation to PA remain to be fully elucidated. The aim of this study was to systematically examine the relationship between CRF and plasma metabolite patterns in 252 healthy adults from the cross-sectional Karlsruhe Metabolomics and Nutrition (KarMeN) study. CRF was determined by measuring the peak oxygen uptake during incremental exercise. Fasting plasma samples were analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry coupled to one- or two-dimensional gas chromatography or liquid chromatography. Based on this multi-platform metabolomics approach, 427 plasma analytes were detected. Bi- and multivariate association analyses, adjusted for age and menopausal status, showed that CRF was linked to specific sets of metabolites primarily indicative of lipid metabolism. However, CRF-related metabolite patterns largely differed between sexes. While several phosphatidylcholines were linked to CRF in females, single lyso-phosphatidylcholines and sphingomyelins were associated with CRF in males. When controlling for further assessed clinical and phenotypical parameters, sex-specific CRF tended to be correlated with a smaller number of metabolites linked to lipid, amino acid, or xenobiotics-related metabolism. Interestingly, sex-specific CRF explanation models could be improved when including selected plasma analytes in addition to clinical and phenotypical variables. In summary, this study revealed sex-related differences in CRF-associated plasma metabolite patterns and proved known associations between CRF and risk factors for cardiometabolic diseases such as fat mass, visceral adipose tissue mass, or blood triglycerides in metabolically healthy individuals. Our findings indicate that covariates like sex and, especially, body composition have to be considered when studying blood metabolic markers related to CRF.

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Relationship between the Cardiorespiratory Fitness and Plasma Metabolite Patterns in Healthy Humans—Results of the KarMeN Study

et al. 2021

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“…Long-chain acylcarnitines, the transport form of cytosolic long-chain FAs into mitochondria, play critical roles in cardiac metabolism and the supply of energy since they are the predominant source of ATP production in cardiac mitochondria via β-oxidation [31]. Recently, LCACs were described as blood-circulating biomarkers associated with cardiovascular diseases [39][40][41]. However, whether LCACs directly affect myocardial function, and particularly whether this effect is positively or negatively inotropic, is undecided [42].…”

Section: Discussionmentioning

confidence: 99%

Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish

Park

Gahr

Krause

et al. 2021

IJMS

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In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.

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“…One reason for this could be ~2-fold decrease in free fatty acid content in KO pancreatic mitochondria (Figure 7J), likely a consequence of reduced availability of lipid droplets (Figures S2, S3) that deliver free fatty acids to mitochondria (51). With LC-MS/GC-MS, we also showed increased levels of long-chain acylcarnitines in KO pancreas (Figure 7K), an indication of impaired β-oxidation (52,53).…”

Section: Gnptab Ablation Causes Mitochondrial Dysfunction In Pancreasmentioning

confidence: 87%

Dysregulation of mannose-6-phosphate–dependent cholesterol homeostasis in acinar cells mediates pancreatitis

Mareninova¹,

Végh²,

Shalbueva³

et al. 2021

Journal of Clinical Investigation

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Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene coding for a key enzyme in M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of non-esterified cholesterol in lysosomes/autolysosomes, its' depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab -/and experimental models involve disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab -/liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab -/mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.

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L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine

Cited by 190 publications

References 135 publications

Sex-Specific Relationship between the Cardiorespiratory Fitness and Plasma Metabolite Patterns in Healthy Humans—Results of the KarMeN Study

Sex-Specific Relationship between the Cardiorespiratory Fitness and Plasma Metabolite Patterns in Healthy Humans—Results of the KarMeN Study

Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish

Dysregulation of mannose-6-phosphate–dependent cholesterol homeostasis in acinar cells mediates pancreatitis

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