Abstract
Peroxisomes play a central role in metabolism as exemplified by the fact that many genetic disorders in humans have been identified through the years in which there is an impairment in one or more of these peroxisomal functions, in most cases associated with severe clinical signs and symptoms. One of the key functions of peroxisomes is the β-oxidation of fatty acids which differs from the oxidation of fatty acids in mitochondria in many respects which includes the different substrate specificities of the two organelles. Whereas mitochondria are the main site of oxidation of medium-and long-chain fatty acids, peroxisomes catalyse the β-oxidation of a distinct set of fatty acids, including very-long-chain fatty acids, pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid. Peroxisomes require the functional alliance with multiple subcellular organelles to fulfil their role in metabolism. Indeed, peroxisomes require the functional interaction with lysosomes, lipid droplets and the endoplasmic reticulum, since these organelles provide the substrates oxidized in peroxisomes. On the other hand, since peroxisomes lack a citric acid cycle as well as respiratory chain, oxidation of the end-products of peroxisomal fatty acid oxidation notably acetyl-CoA, and different medium-chain acyl-CoAs, to CO2 and H2O can only occur in mitochondria. The same is true for the reoxidation of NADH back to NAD+. There is increasing evidence that these interactions between organelles are mediated by tethering proteins which bring organelles together in order to allow effective exchange of metabolites. It is the purpose of this review to describe the current state of knowledge about the role of peroxisomes in fatty acid oxidation, the transport of metabolites across the peroxisomal membrane, its functional interaction with other subcellular organelles and the disorders of peroxisomal fatty acid β-oxidation identified so far in humans.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
De Duve C, Baudhuin P (1966) Peroxisomes (microbodies and related particles). Physiol Rev 46:323–357
Lazarow PB, De Duve C (1976) A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug. Proc Natl Acad Sci 73:2043–2046
Brown FR, van Duyn MAS, Moser AB, Schulman JD, Rizzo WB, Snyder RD, Murphy JV, Kamoshita S, Migeon CJ (1982) Adrenoleukodystrophy: effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids. Johns Hopkins Med J 151:164–172
Heymans HS, Schutgens RB, Tan R, van den Bosch H, Borst P (1983) Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome). Nature 306:69–70
Wanders RJA, Waterham HR (2006) Biochemistry of Mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332
Van Veldhoven PP, Just WW, Mannaerts GP (1987) Permeability of the peroxisomal membrane to cofactors of beta-oxidation. Evidence for the presence of a pore-forming protein. J Biol Chem 262:4310–4318
Verleur N, Wanders RJ (1993) Permeability properties of peroxisomes in digitonin-permeabilized rat hepatocytes. Evidence for free permeability towards a variety of substrates. Eur J Biochem 218:75–82
Antonenkov VD, Sormunen RT, Hiltunen JK (2004) The rat liver peroxisomal membrane forms a permeability barrier for cofactors but not for small metabolites in vitro. J Cell Sci 117:5633–5642
Antonenkov VD, Hiltunen JK (2006) Peroxisomal membrane permeability and solute transfer. Biochim Biophys Acta 1763:1697–1706
Rokka A, Antonenkov VD, Soininen R, Immonen HL, Pirilä PL, Bergmann U, Sormunen RT, Weckström M, Benz R, Hiltunen JK (2009) Pxmp2 is a channel-forming protein in Mammalian peroxisomal membrane. PLoS One 4:e5090
Mindthoff S, Grunau S, Steinfort LL, Girzalsky W, Hiltunen JK, Erdmann R, Antonenkov VD (2016) Peroxisomal Pex11 is a pore-forming protein homologous to TRPM channels. Biochim Biophys Acta, Mol Cell Res 1863:271–283
van Roermund CW, Elgersma Y, Singh N, Wanders RJ, Tabak HF (1995) The membrane of peroxisomes in Saccharomyces cerevisiae is impermeable to NAD(H) and acetyl-CoA under in vivo conditions. EMBO J 14:3480–3486
Verleur N, Hettema EH, van Roermund CW, Tabak HF, Wanders RJ (1997) Transport of activated fatty acids by the peroxisomal ATP-binding-cassette transporter Pxa2 in a semi-intact yeast cell system. Eur J Biochem 249:657–661
van Roermund CWT (1998) Peroxisomal beta-oxidation of polyunsaturated fatty acids in Saccharomyces cerevisiae: isocitrate dehydrogenase provides NADPH for reduction of double bonds at even positions. EMBO J 17:677–687
Wolvetang EJ, Tager JM, Wanders RJ (1990) Latency of the peroxisomal enzyme acyl-CoA:dihydroxyacetonephosphate acyltransferase in digitonin-permeabilized fibroblasts: the effect of ATP and ATPase inhibitors. Biochem Biophys Res Commun 170:1135–1143
Wiesinger C, Kunze M, Regelsberger G, Forss-Petter S, Berger J (2013) Impaired very long-chain acyl-CoA β-oxidation in human X-linked Adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction. J Biol Chem 288:19269–19279
van Roermund CWT, Visser WF, Ijlst L, van Cruchten A, Boek M, Kulik W, Waterham HR, Wanders RJA (2008) The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters. FASEB J 22:4201–4208
van Roermund CWT, Visser WF, IJlst L, Waterham HR, Wanders RJA (2011) Differential substrate specificities of human ABCD1 and ABCD2 in peroxisomal fatty acid β-oxidation. Biochim Biophys Acta Mol Cell Biol Lipids 1811:148–152
Fourcade S, Ruiz M, Camps C et al (2009) A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis. Am J Physiol Endocrinol Metab 296:E211–E221
van Roermund CWT, Ijlst L, Wagemans T, Wanders RJA, Waterham HR (2014) A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids. Biochim Biophys Acta 1841:563–568
Ferdinandusse S, Jimenez-Sanchez G, Koster J et al (2015) A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. Hum Mol Genet 24:361–370
Agrimi G, Russo A, Scarcia P, Palmieri F (2012) The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+. Biochem J 443:241–247
Van Veldhoven PP, de Schryver E, Young SG, Zwijsen A, Fransen M, Espeel M, Baes M, Van Ael E (2020) Slc25a17 gene trapped mice: PMP34 plays a role in the peroxisomal degradation of phytanic and pristanic acid. Front Cell Dev Biol 8:144
DeLoache WC, Russ ZN, Dueber JE (2016) Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways. Nat Commun 7:11152
Van Veldhoven PP (2010) Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res 51:2863–2895
Wanders RJA, Waterham HR, Ferdinandusse S (2016) Metabolic interplay between peroxisomes and other subcellular organelles including mitochondria and the endoplasmic reticulum. Front Cell Dev Biol 3:83
Violante S, Achetib N, van Roermund CWT et al (2019) Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J 33:4355–4364
Ferdinandusse S, Denis S, van Roermund CWTT, Preece MA, Koster J, Ebberink MS, Waterham HR, Wanders RJAA (2018) A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase. Biochim Biophys Acta 1864:952–958
Kim JT, Won SY, Kang KW et al (2020) ACOX3 dysfunction as a potential cause of recurrent spontaneous vasospasm of internal carotid artery. Transl Stroke Res 11(5):1041–1051. https://doi.org/10.1007/s12975-020-00779-z
Ferdinandusse S, Denis S, Van Roermund CWT, Wanders RJA, Dacremont G (2004) Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids. J Lipid Res 45:1104–1111
Houten SM, Denis S, Argmann CA, Jia Y, Ferdinandusse S, Reddy JK, Wanders RJA (2012) Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids. J Lipid Res 53:1296–1303
Ofman R, Dijkstra IME, van Roermund CWT, Burger N, Turkenburg M, van Cruchten A, van Engen CE, Wanders RJA, Kemp S (2010) The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy. EMBO Mol Med 2:90–97
Gronemeyer T, Wiese S, Ofman R et al (2013) The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey. PLoS One 8:e57395
Costello JL, Castro IG, Hacker C et al (2017) ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. J Cell Biol 216:331–342
Hua R, Cheng D, Coyaud É et al (2017) VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis. J Cell Biol 216:367–377
Ferdinandusse S, Falkenberg KD, Koster J et al (2017) ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J Med Genet 54:330–337
Shai N, Yifrach E, van Roermund CWT et al (2018) Systematic mapping of contact sites reveals tethers and a function for the peroxisome-mitochondria contact. Nat Commun 9:1761
Al-Saryi NA, Al-Hejjaj MY, van Roermund CWT, Hulmes GE, Ekal L, Payton C, Wanders RJA, Hettema EH (2017) Two NAD-linked redox shuttles maintain the peroxisomal redox balance in Saccharomyces cerevisiae. Sci Rep 7:11868
Baumgart E, Fahimi HD, Stich A, Völkl A (1996) L-lactate dehydrogenase A4- and A3B isoforms are bona fide peroxisomal enzymes in rat liver. Evidence for involvement in intraperoxisomal NADH reoxidation. J Biol Chem 271:3846–3855
Schueren F, Lingner T, George R, Hofhuis J, Dickel C, Gärtner J, Thoms S (2014) Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals. elife 3:e03640
Schueren F, Thoms S (2016) Functional translational readthrough: a systems biology perspective. PLoS Genet 12:e1006196
Chu B-B, Liao Y-C, Qi W, Xie C, Du X, Wang J, Yang H, Miao H-H, Li B-L, Song B-L (2015) Cholesterol transport through lysosome-peroxisome membrane contacts. Cell 161:291–306
Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M (2016) Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol 12:606–615
Huffnagel IC, Dijkgraaf MGW, Janssens GE, van Weeghel M, van Geel BM, Poll-The BT, Kemp S, Engelen M (2019) Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis 14:30
Engelen M, Barbier M, Dijkstra IME et al (2014) X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain 137:693–706
Huffnagel IC, van Ballegoij WJC, van Geel BM, Vos JMBW, Kemp S, Engelen M (2019) Progression of myelopathy in males with adrenoleukodystrophy: towards clinical trial readiness. Brain 142:334–343
de Beer M, Engelen M, van Geel BM (2014) Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. Neurology 83:2227–2231
Eichler F, Duncan C, Musolino PL et al (2017) Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 377:1630–1638
Hubbard WC, Moser AB, Liu AC et al (2009) Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab 97:212–220
Sandlers Y, Moser AB, Hubbard WC, Kratz LE, Jones RO, Raymond GV (2012) Combined extraction of acyl carnitines and 26:0 lysophosphatidylcholine from dried blood spots: prospective newborn screening for X-linked adrenoleukodystrophy. Mol Genet Metab 105:416–420
Huffnagel IC, van de Beek M-C, Showers AL et al (2017) Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy. Mol Genet Metab 122:209–215
Poll-The BT, Roels F, Ogier H, Scotto J, Vamecq J, Schutgens RB, Wanders RJ, van Roermund CW, van Wijland MJ, Schram AW (1988) A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J Hum Genet 42:422–434
Ferdinandusse S, Denis S, Hogenhout EM, Koster J, van Roermund CWT, IJlst L, Moser AB, Wanders RJA, Waterham HR (2007) Clinical, biochemical, and mutational spectrum of peroxisomal acyl–coenzyme A oxidase deficiency. Hum Mutat 28:904–912
Wanders RJ, Heymans HS, Schutgens RB, Barth PG, van den Bosch H, Tager JM (1988) Peroxisomal disorders in neurology. J Neurol Sci 88:1–39
Ferdinandusse S, Barker S, Lachlan K, Duran M, Waterham HR, Wanders RJA, Hammans S (2010) Adult peroxisomal acyl-coenzyme A oxidase deficiency with cerebellar and brainstem atrophy. J Neurol Neurosurg Psychiatry 81:310–312
Vilarinho S, Sari S, Mazzacuva F et al (2016) ACOX2 deficiency: a disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment. Proc Natl Acad Sci 113:11289–11293
Monte MJ, Alonso-Peña M, Briz O, Herraez E, Berasain C, Argemi J, Prieto J, Marin JJGG (2017) ACOX2 deficiency: an inborn error of bile acid synthesis identified in an adolescent with persistent hypertransaminasemia. J Hepatol 66:581–588
Suzuki Y, Jiang LL, Souri M et al (1997) D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency: a newly identified peroxisomal disorder. Am J Hum Genet 61:1153–1162
van Grunsven EG, van Berkel E, Ijlst L, Vreken P, de Klerk JB, Adamski J, Lemonde H, Clayton PT, Cuebas DA, Wanders RJ (1998) Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency. Proc Natl Acad Sci USA 95:2128–2133
Goldfischer S, Collins J, Rapin I, Neumann P, Neglia W, Spiro AJ, Ishii T, Roels F, Vamecq J, Van Hoof F (1986) Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities. J Pediatr 108:25–32
Ferdinandusse S, van Grunsven EG, Oostheim W, Denis S, Hogenhout EM, IJlst L, van Roermund CWT, Waterham HR, Goldfischer S, Wanders RJA (2002) Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of d-bifunctional protein. Am J Hum Genet 70:1589–1593
Ferdinandusse S, Denis S, Mooyer PAW et al (2006) Clinical and biochemical spectrum of D-bifunctional protein deficiency. Ann Neurol 59:92–104
Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King M-C (2010) Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault syndrome. Am J Hum Genet 87:282–288
McMillan HJ, Worthylake T, Schwartzentruber J et al (2012) Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J Rare Dis 7:90
Lines MA, Jobling R, Brady L et al (2014) Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing. Neurology 82:963–968
Ferdinandusse S, Ebberink MS, Vaz FM, Waterham HR, Wanders RJA (2016) The important role of biochemical and functional studies in the diagnostics of peroxisomal disorders. J Inherit Metab Dis 39:531–543
Setchell KDR, Heubi JE, Bove KE, O’Connell NC, Brewsaugh T, Steinberg SJ, Moser A, Squires RH (2003) Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology 124:217–232
Ferdinandusse S, Denis S, Clayton PT et al (2000) Mutations in the gene encoding peroxisomal α-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 24:188–191
Haugarvoll K, Johansson S, Tzoulis C, Haukanes BI, Bredrup C, Neckelmann G, Boman H, Knappskog PM, Bindoff LA (2013) MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing. Orphanet J Rare Dis 8:1
Vaz FM, Ferdinandusse S (2017) Bile acid analysis in human disorders of bile acid biosynthesis. Mol Asp Med 56:10–24
Ferdinandusse S, Kostopoulos P, Denis S et al (2006) Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Am J Hum Genet 78:1046–1052
Horvath R, Lewis-Smith D, Douroudis K, Duff J, Keogh M, Pyle A, Fletcher N, Chinnery PF (2015) SCP2 mutations and neurodegeneration with brain iron accumulation. Neurology 85:1909–1911
Seedorf U, Brysch P, Engel T, Schrage K, Assmann G (1994) Sterol carrier protein X is peroxisomal 3-oxoacyl coenzyme A thiolase with intrinsic sterol carrier and lipid transfer activity. J Biol Chem 269:21277–21283
Wanders RJ, Denis S, Wouters F, Wirtz KW, Seedorf U (1997) Sterol carrier protein X (SCPx) is a peroxisomal branched-chain beta-ketothiolase specifically reacting with 3-oxo-pristanoyl-CoA: a new, unique role for SCPx in branched-chain fatty acid metabolism in peroxisomes. Biochem Biophys Res Commun 236:565–569
Antonenkov VD, Van Veldhoven PP, Waelkens E, Mannaerts GP (1997) Substrate specificities of 3-oxoacyl-CoA thiolase A and sterol carrier protein 2/3-oxoacyl-CoA thiolase purified from normal rat liver peroxisomes. Sterol carrier protein 2/3-oxoacyl-CoA thiolase is involved in the metabolism of 2-methyl-branched fatty ac. J Biol Chem 272:26023–26031
Abu-Safieh L, Alrashed M, Anazi S et al (2013) Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res 23:236–247
Yagita Y, Shinohara K, Abe Y, Nakagawa K, Al-Owain M, Alkuraya FS, Fujiki Y (2017) Deficiency of a retinal dystrophy protein, acyl-CoA binding domain-containing 5 (ACBD5), impairs peroxisomal β-oxidation of very-long-chain fatty acids. J Biol Chem 292:691–705
Argyriou C, D’Agostino MD, Braverman N (2016) Peroxisome biogenesis disorders. Transl Sci Rare Dis 1:111–144
Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT (2015) Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis 10:151
Klouwer FCC, Huffnagel IC, Ferdinandusse S, Waterham HR, Wanders RJA, Engelen M, Poll-The BT (2016) Clinical and biochemical pitfalls in the diagnosis of peroxisomal disorders. Neuropediatrics 47:205–220
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Wanders, R.J.A., Vaz, F.M., Waterham, H.R., Ferdinandusse, S. (2020). Fatty Acid Oxidation in Peroxisomes: Enzymology, Metabolic Crosstalk with Other Organelles and Peroxisomal Disorders. In: Lizard, G. (eds) Peroxisome Biology: Experimental Models, Peroxisomal Disorders and Neurological Diseases. Advances in Experimental Medicine and Biology, vol 1299. Springer, Cham. https://doi.org/10.1007/978-3-030-60204-8_5
Download citation
DOI: https://doi.org/10.1007/978-3-030-60204-8_5
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-60203-1
Online ISBN: 978-3-030-60204-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)