Prostaglandins, Leukotrienes and Essential Fatty Acids
Volume 81, Issue 4 , Pages 253-264 , October 2009

Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism

  • Élodie Pastural

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Shawn Ritchie

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Yingshen Lu

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Wei Jin

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Amir Kavianpour

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Khine Khine Su-Myat

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Doug Heath

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Paul L. Wood

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
  • ,
  • Maura Fisk

      Affiliations

    • Jonty Foundation, Saint-Paul, MN, USA
  • ,
  • Dayan B. Goodenowe

      Affiliations

    • Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
    • Corresponding Author InformationCorresponding author. Tel.: +13062448233; fax: +13062446730.

Received 7 April 2009 ,Revised 12 June 2009 ,Accepted 15 June 2009.

References 

  1. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, fourth ed., 1994.
  2. Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of autism in a US metropolitan area. Jama. 2003;289(1):49–55
  3. DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, et al. The developmental neurobiology of autism spectrum disorder. J. Neurosci. 2006;26(26):6897–6906
  4. Fombonne E. Epidemiological surveys of autism and other pervasive developmental disorders: an update. J. Autism. Dev. Disord. 2003;33(4):365–382
  5. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 2005;57(1):67–81
  6. Palmen SJ, Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism. Brain. 2004;127(Part 12):2572–2583
  7. Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr. Opin. Neurobiol. 1997;7(2):269–278
  8. Courchesne E, Redcay E, Kennedy DP. The autistic brain: birth through adulthood. Curr. Opin. Neurol. 2004;17(4):489–496
  9. Herbert MR, Ziegler DA, Makris N, Filipek PA, Kemper TL, Normandin JJ, et al. Localization of white matter volume increase in autism and developmental language disorder. Ann. Neurol. 2004;55(4):530–540
  10. Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot. Essent. Fatty Acids. 2002;67(5):341–343
  11. Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin – the antioxidant proteins. Life Sci. 2004;75(21):2539–2549
  12. Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13(3):171–181
  13. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am. J. Clin. Nutr. 2004;80(6):1611–1617
  14. Sogut S, Zoroglu SS, Ozyurt H, Yilmaz HR, Ozugurlu F, Sivasli E, et al. Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin. Chim. Acta. 2003;331(1–2):111–117
  15. Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O, et al. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur. Arch. Psychiatry Clin. Neurosci. 2004;254(3):143–147
  16. Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G, Anckarsater H, et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol. Psychiatry. 2008;13(1):90–98
  17. Sliwinski S, Croonenberghs J, Christophe A, Deboutte D, Maes M. Polyunsaturated fatty acids: do they have a role in the pathophysiology of autism?. Neuro. Endocrinol. Lett. 2006;27(4):465–471
  18. Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J. Toxicol. Environ. Health B Crit. Rev. 2006;9(6):485–499
  19. Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int. J. Dev. Neurosci. 2005;23(2–3):183–187
  20. Aharoni A, Ric de Vos CH, Verhoeven HA, Maliepaard CA, Kruppa G, Bino R, et al. Nontargeted metabolome analysis by use of fourier transform Ion cyclotron mass spectrometry. Omics. 2002;6(3):217–234
  21. Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, et al. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia. J. Lipid Res. 2007;48(11):2485–2498
  22. Wood PL, Khan MA, Moskal JR. Neurochemical analysis of amino acids, polyamines and carboxylic acids: GC–MS quantitation of tBDMS derivatives using ammonia positive chemical ionization. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2006;831:313–319
  23. Geier DA, Geier MR. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Horm. Res. 2006;66(4):182–188
  24. Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ. Relative carnitine deficiency in autism. J. Autism. Dev. Disord. 2004;34(6):615–623
  25. Tirosh O, Sen CK, Roy S, Packer L. Cellular and mitochondrial changes in glutamate-induced HT4 neuronal cell death. Neuroscience. 2000;97(3):531–541
  26. Lumeng L, Bremer J, Davis EJ. Suppression of the mitochondrial oxidation of (-)-palmitylcarnitine by the malate-aspartate and alpha-glycerophosphate shuttles. J. Biol. Chem. 1976;251(2):277–284
  27. Vickers AE, Bentley P, Fisher RL. Consequences of mitochondrial injury induced by pharmaceutical fatty acid oxidation inhibitors is characterized in human and rat liver slices. Toxicol. In Vitro. 2006;20(7):1173–1182
  28. Skorin C, Necochea C, Johow V, Soto U, Grau AM, Bremer J, et al. Peroxisomal fatty acid oxidation and inhibitors of the mitochondrial carnitine palmitoyltransferase I in isolated rat hepatocytes. Biochem. J. 1992;281(Part 2):561–567
  29. Hayashi H, Hara M. 1-Alkenyl group of ethanolamine plasmalogen derives mainly from de novo-synthesized fatty alcohol within peroxisomes, but not extraperoxisomal fatty alcohol or fatty acid. J. Biochem. (Tokyo). 1997;121(5):978–983
  30. Singh H, Beckman K, Poulos A. Exclusive localization in peroxisomes of dihydroxyacetone phosphate acyltransferase and alkyl-dihydroxyacetone phosphate synthase in rat liver. J. Lipid Res. 1993;34(3):467–477
  31. Voss A, Reinhart M, Sankarappa S, Sprecher H. The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase. J. Biol. Chem. 1991;266(30):19995–20000
  32. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113(5):e472–e486
  33. Domercq M, Sanchez-Gomez MV, Sherwin C, Etxebarria E, Fern R, Matute C. System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J. Immunol. 2007;178(10):6549–6556
  34. Matute C, Alberdi E, Domercq M, Sanchez-Gomez MV, Perez-Samartin A, Rodriguez-Antiguedad A, et al. Excitotoxic damage to white matter. J. Anat. 2007;210(6):693–702
  35. Bremer J, Wojtczak AB. Factors controlling the rate of fatty acid-oxidation in rat liver mitochondria. Biochim. Biophys. Acta. 1972;280(4):515–530
  36. Bartlett K, Eaton S. Mitochondrial beta-oxidation. Eur. J. Biochem. 2004;271(3):462–469
  37. Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, et al. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J. Biol. Chem. 1998;273(10):5678–5684
  38. Kondrup J, Lazarow PB. Flux of palmitate through the peroxisomal and mitochondrial beta-oxidation systems in isolated rat hepatocytes. Biochim. Biophys. Acta. 1985;835(1):147–153
  39. Hayashi H, Takahata S. Role of peroxisomal fatty acyl-CoA beta-oxidation in phospholipid biosynthesis. Arch. Biochem. Biophys. 1991;284(2):326–331
  40. Reszko AE, Kasumov T, David F, Jobbins KA, Thomas KR, Hoppel CL, et al. Peroxisomal fatty acid oxidation is a substantial source of the acetyl moiety of malonyl-CoA in rat heart. J. Biol. Chem. 2004;279(19):19574–19579
  41. Hayashi H, Oohashi M. Incorporation of acetyl-CoA generated from peroxisomal beta-oxidation into ethanolamine plasmalogen of rat liver. Biochim. Biophys. Acta. 1995;1254(3):319–325
  42. Hayashi H, Sato A. Fatty alcohol synthesis accompanied with chain elongation in liver peroxisomes. Biochim. Biophys. Acta. 1997;1346(1):38–44
  43. Sprecher H, Luthria DL, Mohammed BS, Baykousheva SP. Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids. J. Lipid Res. 1995;36(12):2471–2477
  44. Gaposchkin DP, Zoeller RA. Plasmalogen status influences docosahexaenoic acid levels in a macrophage cell line. Insights using ether lipid-deficient variants. J. Lipid Res. 1999;40(3):495–503
  45. Moser HW, Moser AB. Very long-chain fatty acids in diagnosis, pathogenesis, and therapy of peroxisomal disorders. Lipids. 1996;31(Suppl.):S141–S144
  46. Kemp S, Valianpour F, Denis S, Ofman R, Sanders RJ, Mooyer P, et al. Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol. Genet. Metab. 2005;84(2):144–151
  47. Hostetler HA, Kier AB, Schroeder F. Very-long-chain and branched-chain fatty acyl-CoAs are high affinity ligands for the peroxisome proliferator-activated receptor alpha (PPARalpha). Biochemistry. 2006;45(24):7669–7681
  48. Wang Y, Botolin D, Xu J, Christian B, Mitchell E, Jayaprakasam B, et al. Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J. Lipid Res. 2006;47(9):2028–2041
  49. Wang Y, Botolin D, Christian B, Busik J, Xu J, Jump DB. Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases. J. Lipid Res. 2005;46(4):706–715
  50. Pettegrew JW, Levine J, McClure RJ. Acetyl-l-carnitine physical–chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol. Psychiatry. 2000;5(6):616–632
  51. Nalecz KA, Nalecz MJ. Carnitine – a known compound, a novel function in neural cells.. Acta Neurobiol. Exp. (Wars). 1996;56(2):597–609
  52. Bremer J. The role of carnitine in intracellular metabolism. J. Clin. Chem. Clin. Biochem. 1990;28(5):297–301
  53. Bieber LL. Carnitine. Annu. Rev. Biochem. 1988;57:261–283
  54. Bourre JM, Piciotti M. Delta-6 desaturation of alpha-linolenic acid in brain and liver during development and aging in the mouse. Neurosci. Lett. 1992;141(1):65–68
  55. Scott BL, Bazan NG. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc. Natl. Acad. Sci. USA. 1989;86(8):2903–2907
  56. Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, Marques C, et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev. Med. Child Neurol. 2005;47(3):185–189
  57. Dumser M, Bauer J, Lassmann H, Berger J, Forss-Petter S. Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency. Acta Neuropathol. 2007;114(6):573–586
  58. Singh J, Khan M, Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy. J. Lipid Res. 2008;
  59. Ferrer I, Kapfhammer JP, Hindelang C, Kemp S, Troffer-Charlier N, Broccoli V, et al. Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage. Hum. Mol. Genet. 2005;14(23):3565–3577
  60. Liang J, Takeuchi H, Doi Y, Kawanokuchi J, Sonobe Y, Jin S, et al. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res. 2008;1210:11–19
  61. Piani D, Fontana A. Involvement of the cystine transport system xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J. Immunol. 1994;152(7):3578–3585
  62. Zhao W, Xie W, Le W, Beers DR, He Y, Henkel JS, et al. Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J. Neuropathol. Exp. Neurol. 2004;63(9):964–977
  63. Brown DR. Neurons depend on astrocytes in a coculture system for protection from glutamate toxicity. Mol. Cell Neurosci. 1999;13(5):379–389
  64. Rosenberg PA, Aizenman E. Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 1989;103(2):162–168
  65. Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J. Clin. Psychiatry. 2005;66(Suppl. 10):3–8
  66. Fombonne E. The epidemiology of autism: a review. Psychol. Med. 1999;29(4):769–786
  67. Ritvo ER, Freeman BJ, Pingree C, Mason-Brothers A, Jorde L, Jenson WR, et al. The UCLA-University of Utah epidemiologic survey of autism: prevalence. Am. J. Psychiatry. 1989;146(2):194–199
  68. Horlick MB, Rosenbaum M, Nicolson M, Levine LS, Fedun B, Wang J, et al. Effect of puberty on the relationship between circulating leptin and body composition. J. Clin. Endocrinol. Metab. 2000;85(7):2509–2518
  69. Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler GB. Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J. Clin. Invest. 1994;94(6):2475–2480
  70. Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J. Neurochem. 1996;66(5):1836–1844
  71. Harms C, Lautenschlager M, Bergk A, Katchanov J, Freyer D, Kapinya K, et al. Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration. J. Neurosci. 2001;21(8):2600–2609
  72. Hilton GD, Ndubuizu AN, McCarthy MM. Neuroprotective effects of estradiol in newborn female rat hippocampus. Brain Res. Dev. Brain Res. 2004;150(2):191–198
  73. McClean J, Nunez JL. 17alpha-Estradiol is neuroprotective in male and female rats in a model of early brain injury. Exp. Neurol. 2008;210(1):41–50
  74. Mendelowitsch A, Ritz MF, Ros J, Langemann H, Gratzl O. 17beta-Estradiol reduces cortical lesion size in the glutamate excitotoxicity model by enhancing extracellular lactate: a new neuroprotective pathway. Brain Res. 2001;901(1–2):230–236
  75. Nilsen J, Diaz Brinton R. Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Proc. Natl. Acad. Sci. USA. 2003;100(5):2842–2847
  76. Singer CA, Rogers KL, Strickland TM, Dorsa DM. Estrogen protects primary cortical neurons from glutamate toxicity. Neurosci. Lett. 1996;212(1):13–16
  77. Vavaiya KV, Briski KP. Effects of caudal hindbrain lactate infusion on insulin-induced hypoglycemia and neuronal substrate transporter glucokinase and sulfonylurea receptor-1 gene expression in the ovariectomized female rat dorsal vagal complex: impact of estradiol. J. Neurosci. Res. 2008;86(3):694–701
  78. Zhang Y, Lu X, Bhavnani BR. Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death. BMC Neurosci. 2003;4:32
  79. Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ, et al. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice. J. Clin. Invest. 1998;102(6):1083–1091
  80. Schneider GH, Baethmann A, Kempski O. Mechanisms of glial swelling induced by glutamate. Can. J. Physiol. Pharmacol. 1992;70(Suppl.):S334–S343
  81. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Geier MRA. Prospective study of transsulfuration biomarkers in autistic disorders. Neurochem. Res. 2008;
  82. Chen CJ, Liao SL, Kuo JS. Gliotoxic action of glutamate on cultured astrocytes. J. Neurochem. 2000;75(4):1557–1565
  83. Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot. Essent. Fatty Acids. 2005;379(5):379–384
  84. Wood PL, Khan MA, Kulow SR, Mahmood SA, Moskal JR. Neurotoxicity of reactive aldehydes: the concept of “aldehyde load” as demonstrated by neuroprotection with hydroxylamines. Brain Res. 2006;1095(1):190–199
  85. Dringen R. Oxidative and antioxidative potential of brain microglial cells. Antioxidants Redox Signaling***. 2005;7(9–10):1223–1233
  86. Eichler FS, Ren JQ, Cossoy M, Rietsch AM, Nagpal S, Moser AB, et al. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?. Ann. Neurol. 2008;63(6):729–742
  87. Brites P, Mooyer PAW, Mrabet L, Waterham HR, Wanders RJA. Plasmalogens participate in very-long-chain fatty acid-induced pathology.. Brain. 2009;132:482–492
  88. Blaylock RL. A possible central mechanism in autism spectrum disorders, Part I. Altern. Ther. Health Med. 2008;14(6):46–53

PII: S0952-3278(09)00111-2

doi: 10.1016/j.plefa.2009.06.003

Prostaglandins, Leukotrienes and Essential Fatty Acids
Volume 81, Issue 4 , Pages 253-264 , October 2009