Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

Abstract

In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine dimunition was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete ␤-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.Disturbances in mitochondrial genesis, morphology, and function are increasingly recognized as components of insulin resistance and the metabolic syndrome (1-3). Still unclear is whether poor mitochondrial performance is a predisposing factor or a consequence of the disease process. The latter view is supported by recent animal studies linking diet-induced insulin resistance to a dysregulated mitochondrial phenotype in skeletal muscle, marked by excessive ␤-oxidation, impaired substrate switching during the fasted to fed transition, and coincident reduction of organic acid intermediates of the tricarboxylic acid cycle (4, 5). In these studies, both diet-induced and genetic forms of insulin resistance were specifically linked to high rates of incomplete fat oxidation and intramuscular accumulation of fatty acylcarnitines, byproducts of lipid catabolism that are produced under conditions of metabolic stress (5, 6). Most compelling, we showed that genetically engineered inhibition of fat oxidation lowered intramuscular acylcarnitine levels and preserved glucose tolerance in mice fed a high fat diet (5, 7). In aggregate, the findings established a stron...

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

“…Previous studies have identified numerous metabolic regulatory proteins as targets for repression by miR-378 and miR-378* (10,(26)(27)(28). In addition, we found that carnitine O-acetyltransferase (CRAT), a mitochondrial enzyme involved in fatty acid metabolism (29,30), and MED13 are repressed by miR-378 and miR-378*, respectively. Our findings indicate that miR-378 and miR-378* function to control the overall oxidative capacity of metabolically active tissues during periods of dietary stress.…”

“…4A). CRAT channels the products of β-oxidation to the TCA cycle, away from mitochondrial efflux, thereby coupling mitochondrial fatty acid uptake to oxidative metabolism (29,30,39). Reduced CRAT activity has been identified as a reversible abnormality of the metabolic syndrome (29).…”

“…CRAT channels the products of β-oxidation to the TCA cycle, away from mitochondrial efflux, thereby coupling mitochondrial fatty acid uptake to oxidative metabolism (29,30,39). Reduced CRAT activity has been identified as a reversible abnormality of the metabolic syndrome (29). Perturbation of metabolic homeostasis by HFD is associated with compromised mitochondrial fuel metabolism and incomplete fatty acid oxidation owing to reduced carnitine levels (29,30).…”

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…Importantly, these LCAC metabolites were significantly higher in HFrEF than HFpEF, inversely related to LVEF. As a reflection of impaired or dysregulated FAO, the elevated plasma LCAC observed may suggest a shared metabolic impairment of the HF clinical syndrome independent of LVEF 13, 53, 54. Given that FAO impairments or dysregulation may result from a variety of mitochondrial insults, further investigation will be needed to identify the causal processes underlying the LCAC elevations reported in this study 12, 83.…”

“…Functionally, they facilitate transfer of LCFAs into the mitochondria for ß‐oxidation 52. Although typically short‐lived, LCAC accumulate in states of inefficient fatty acid oxidation (FAO), which may be attributed to (1) defects in mitochondrial FAO enzymes or (2) increased FAO relative to tricarboxylic acid (TCA) flux; this leads to a bottleneck of carbon substrates at the TCA cycle 53, 54. Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57.…”