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Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models

  • Fatty Acid Oxidation
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Mouse models have been designed for a number of fatty acid oxidation defects. Studies in these mouse models have demonstrated that different pathogenetic mechanisms play a role in the pathophysiology of defects of fatty acid oxidation. Supplementation with L-carnitine does not prevent low tissue carnitine levels and induces acylcarnitine production having potentially toxic effects, as presented in very-long-chain acyl-CoA dehydrogenase (VLCAD)-deficient mice. Energy deficiency appears to be an important mechanism in the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation defects and is also the underlying mechanism of cold intolerance. Hypoglycemia as one major clinical sign in all fatty acid oxidation defects occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake rather than to transcriptional changes that are also observed simultaneously, as presented in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice. There are reports that an impaired fatty acid oxidation also plays a role in intrauterine life. The embryonic loss demonstrated for some enzyme defects in the mouse supports this hypothesis. However, the exact mechanisms are unknown. This observation correlates to maternal hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, as observed in pregnancies carrying a long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)-deficient fetus. Synergistic heterozygosity has been shown in isolated patients and in mouse models to be associated with clinical phenotypes common to fatty acid oxidation disorders. Synergistic mutations may also modulate severity of the clinical phenotype and explain in part clinical heterogeneity of fatty acid oxidation defects. In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies.

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Abbreviations

APR:

acute-phase response

CPT-1a:

carnitine palmitoyl-CoA transferase-1a (liver isoform)

CPT-1b:

carnitine palmitoyl-CoA transferase-1b (muscle isoform)

DAG:

diacylglycerol

FAO:

fatty acid oxidation

G-6-P:

glucose-6 phosphate

LCAD:

long-chain acyl-CoA dehydrogenase

LCT:

long-chain triglycerides

MCAD:

medium-chain acyl-CoA dehydrogenase

MCADD:

medium-chain acyl-CoA dehydrogenase deficiency

MCT:

medium-chain triglycerides

PPAR-α:

peroxisomal proliferator activated receptor alpha

PGC1-α:

PPAR-γ coactivator-1 alpha

PDK4:

pyruvate dehydrogenase kinase 4

SCAD:

short-chain acyl-CoA dehydrogenase

TFP:

mitochondrial trifunctional protein

TFPD:

trifunctional protein deficiency

VLCAD:

very-long-chain acyl-CoA dehydrogenase

VLCADD:

very-long-chain acyl-CoA dehydrogenase deficiency

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Acknowledgements

Part of the work supported by grants from the Deutsche Forschungsgemeinschaft to US (DFG, SP1125/1-1; SFB 575; SFB 612). Other parts of the work were supported by National Institutes of Health (NIH) Grant Number RO1-RR02599 and T-32-RR00493 to PAW from the National Center for Research Resources (NCRR), a component of the NIH, and its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

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Authors and Affiliations

  1. Department of General Pediatrics, University Children’s Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany

    Ute Spiekerkoetter

  2. Metabolic Signaling & Disease Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL, USA

    Philip A. Wood

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  1. Ute Spiekerkoetter
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  2. Philip A. Wood
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Correspondence to Ute Spiekerkoetter.

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Communicated by: Verena Peters

Competing interest: None declared.

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Spiekerkoetter, U., Wood, P.A. Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models. J Inherit Metab Dis 33, 539–546 (2010). https://doi.org/10.1007/s10545-010-9121-7

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  • DOI: https://doi.org/10.1007/s10545-010-9121-7

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