The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders

Houten, Sander M.; Violante, Sara; Ventura, Fátima V.; Wanders, Ronald J. A.

doi:10.1146/annurev-physiol-021115-105045

Cited by 557 publications

(461 citation statements)

References 151 publications

(84 reference statements)

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“…At least 20 separate transport proteins and enzymes are required for activation and breakdown of fatty acids via FAO (Table 2) [37]. Fatty acids are transported through the blood as non-esterified fatty acids bound to lipoproteins or serum albumin.…”

Section: Mitochondrial Fatty Acid β-Oxidation (Fao)mentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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Section: Mitochondrial Fatty Acid β-Oxidation (Fao)mentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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“…As beta-oxidation takes place in the mitochondria, FAs are imported from the cytoplasm using carnitine shuttle system, in which carnitine palmitoyltransferase 1 (CPT1) is a component. FA oxidation is regulated at multiple levels, including peroxisome proliferator-activated receptors (PPARs) and coactivators (PGCs), as well as posttranscriptionally, such as through allosteric control of CPT1 by malonyl-CoA (important building block of FA biosynthesis; Foster, 2012), the levels of which are controlled by PPAR and AMPK (Houten, Violante, Ventura, & Wanders, 2016). Other posttranslational regulations of FA oxidation have been proposed including acetylation/deacetylation by SIRT1 and S-nitrosylation by nitric oxide.…”

Section: Contribution Of Amino Acids and Fas To Energy Metabolismmentioning

confidence: 99%

Metabolism of Preimplantation Embryo Development

Kaneko

2016

Current Topics in Developmental Biology

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“…DECRD can be detected in newborn screening (NBS) using C10: 2-carnitine as the screening analite (Houten, Violante, Ventura, & Wanders, 2016; McHugh et al, 2011). Since our patient does not have elevated C10:2-carnitine levels she would not have been detected.…”

Section: Discussionmentioning

confidence: 99%

Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant

Pomerantz¹,

Ferdinandusse

Cogan³

et al. 2018

American J of Med Genetics Pt A

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Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyper-lysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient’s normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes.

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The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders

Cited by 557 publications

References 151 publications

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Metabolism of Preimplantation Embryo Development

Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant

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