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Lipids

, Volume 49, Issue 1, pp 113–117 | Cite as

Autosomal Dominant Inheritance of Brain Cardiolipin Fatty Acid Abnormality in VM/DK Mice: Association with Hypoxic-Induced Cognitive Insensitivity

  • Nathan L. Ta
  • Xibei Jia
  • Michael Kiebish
  • Thomas N. SeyfriedEmail author
Communication

Abstract

Cardiolipin is a complex polyglycerol phospholipid found almost exclusively in the inner mitochondrial membrane and regulates numerous enzyme activities especially those related to oxidative phosphorylation and coupled respiration. Abnormalities in cardiolipin can impair mitochondrial function and bioenergetics. We recently demonstrated that the ratio of shorter chain saturated and monounsaturated fatty acids (C16:0; C18:0; C18:1) to longer chain polyunsaturated fatty acids (C18:2; C20:4; C22:6) was significantly greater in the brains of adult VM/DK (VM) inbred mice than in the brains of C57BL/6 J (B6) mice. The cardiolipin fatty acid abnormalities in VM mice are also associated with alterations in the activity of mitochondrial respiratory complexes. In this study we found that the abnormal brain fatty acid ratio in the VM strain was inherited as an autosomal dominant trait in reciprocal B6 × VM F1 hybrids. To evaluate the potential influence of brain cardiolipin fatty acid composition on cognitive sensitivity, we placed the parental B6 and VM mice and their reciprocal male and female B6VMF1 hybrid mice (3-month-old) in a hypoxic chamber (5 % O2). Cognitive awareness (conscientiousness) under hypoxia was significantly lower in the VM parental mice and F1 hybrid mice (11.4 ± 0.4  and 11.0 ± 0.4 min, respectively) than in the parental B6 mice (15.3 ± 1.4 min), indicating an autosomal dominant inheritance like that of the brain cardiolipin abnormalities. These findings suggest that impaired cognitive awareness under hypoxia is associated with abnormalities in neural lipid composition.

Keywords

GLC (GC) (Gas–liquid chromatography) < Analytical techniques Lipid biochemistry < General area Thin layer chromatography < Analytical techniques Cardiolipin < Specific lipids 

Notes

Acknowledgments

This work was supported in part by grants from the Boston College Research Fund and NIH NS055195.

References

  1. 1.
    Kiebish MA, Han X, Cheng H, Lunceford A, Clarke CF, Moon H, Chuang JH, Seyfried TN (2008) Lipidomic analysis and electron transport chain activities in C57BL/6 J mouse brain mitochondria. J Neurochem 106:299–312PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Berrigan D, Perkins SN, Haines DC, Hursting SD (2002) Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis 23:817–822PubMedCrossRefGoogle Scholar
  3. 3.
    Fry M, Blondin GA, Green DE (1980) The localization of tightly bound cardiolipin in cytochrome oxidase. J Biol Chem 255:9967–9970PubMedGoogle Scholar
  4. 4.
    Fry M, Green DE (1981) Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain. J Biol Chem 256:1874–1880PubMedGoogle Scholar
  5. 5.
    Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292:C33–C44PubMedCrossRefGoogle Scholar
  6. 6.
    Hoch FL (1992) Cardiolipins and biomembrane function. Biochim Biophys Acta 1113:71–133PubMedCrossRefGoogle Scholar
  7. 7.
    Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN (2008) Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res 49:2545–2556PubMedCrossRefGoogle Scholar
  8. 8.
    Hoch FL (1998) Cardiolipins and mitochondrial proton-selective leakage. J Bioenerg Biomembr 30:511–532PubMedCrossRefGoogle Scholar
  9. 9.
    Cheng H, Mancuso DJ, Jiang X, Guan S, Yang J, Yang K, Sun G, Gross RW, Han X (2008) Shotgun lipidomics reveals the temporally dependent, highly diversified cardiolipin profile in the mammalian brain: temporally coordinated postnatal diversification of cardiolipin molecular species with neuronal remodeling. Biochemistry 47:5869–5880PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN (2008) Brain mitochondrial lipid abnormalities in mice susceptible to spontaneous gliomas. Lipids 43:951–959PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Fraser H (1986) Brain tumours in mice, with particular reference to astrocytoma. Food Chem Toxicol 24:105–111PubMedCrossRefGoogle Scholar
  12. 12.
    van Meyel DJ, Sanchez-Sweatman OH, Kerkvliet N, Stitt L, Ramsay DA, Khokha R, Chambers AF, Cairncross JG (1998) Genetic background influences timing, morphology and dissemination of lymphomas in p53-deficient mice. Int J Oncol 13:917–922PubMedGoogle Scholar
  13. 13.
    Mancuso DJ, Kotzbauer P, Wozniak DF, Sims HF, Jenkins CM, Guan S, Han X, Yang K, Sun G, Malik I, Conyers S, Green KG, Schmidt RE, Gross RW (2009) Genetic ablation of calcium-independent phospholipase A2{gamma} leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J Biol Chem 284:35632–35644PubMedCrossRefGoogle Scholar
  14. 14.
    Seyfried TN (2012) Cancer as a metabolic disease: on the origin, management, and prevention of cancer. Wiley, HobokenGoogle Scholar
  15. 15.
    Seyfried TN, Shelton LM (2010) Cancer as a metabolic disease. Nutr Metabol 7:7CrossRefGoogle Scholar
  16. 16.
    Pope S, Land JM, Heales SJ (2008) Oxidative stress and mitochondrial dysfunction in neurodegeneration; cardiolipin a critical target? Biochim Biophys Acta 1777:794PubMedCrossRefGoogle Scholar
  17. 17.
    Daum G (1985) Lipids of mitochondria. Biochim Biophys Acta 822:1–42PubMedCrossRefGoogle Scholar
  18. 18.
    Bayir H, Tyurin VA, Tyurina YY, Viner R, Ritov V, Amoscato AA, Zhao Q, Zhang XJ, Janesko-Feldman KL, Alexander H, Basova LV, Clark RS, Kochanek PM, Kagan VE (2007) Selective early cardiolipin peroxidation after traumatic brain injury: an oxidative lipidomics analysis. Annals Neurol 62:154–169CrossRefGoogle Scholar
  19. 19.
    Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, MacFabe DF (2012) The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflamm 9:153CrossRefGoogle Scholar
  20. 20.
    Petrosillo G, De Benedictis V, Ruggiero FM, Paradies G (2013) Decline in cytochrome c oxidase activity in rat-brain mitochondria with aging: role of peroxidized cardiolipin and beneficial effect of melatonin. J Bioenerg Biomembr 45:431PubMedCrossRefGoogle Scholar
  21. 21.
    Seyfried TN (1979) Audiogenic seizures in mice. Fed Proc 38:2399–2404PubMedGoogle Scholar
  22. 22.
    Seyfried TN, Glaser GH, Yu RK (1978) Cerebral, cerebellar, and brain stem gangliosides in mice susceptible to audiogenic seizures. J Neurochem 31:21–27PubMedCrossRefGoogle Scholar
  23. 23.
    Baek RC, Kasperzyk JL, Platt FM, Seyfried TN (2004) N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. J Neurochem 90(Suppl 1):89Google Scholar
  24. 24.
    Baek RC, Kasperzyk JL, Platt FM, Seyfried TN (2008) N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. Neurochem Int 52:1125–1133PubMedCrossRefGoogle Scholar
  25. 25.
    Macala LJ, Yu RK, Ando S (1983) Analysis of brain lipids by high performance thin-layer chromatography and densitometry. J Lipid Res 24:1243–1250PubMedGoogle Scholar
  26. 26.
    Lepage G, Roy CC (1984) Improved recovery of fatty acid through direct transesterification without prior extraction or purification. J Lipid Res 25:1391–1396PubMedGoogle Scholar
  27. 27.
    Barcelo-Coblijn G, Collison LW, Jolly CA, Murphy EJ (2005) Dietary alpha-linolenic acid increases brain but not heart and liver docosahexaenoic acid levels. Lipids 40:787–798PubMedCrossRefGoogle Scholar
  28. 28.
    Vreken P, Valianpour F, Nijtmans LG, Grivell LA, Plecko B, Wanders RJ, Barth PG (2000) Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. Biochem Biophys Res Commun 279:378–382PubMedCrossRefGoogle Scholar
  29. 29.
    Jump DB (2009) Mammalian fatty acid elongases. Methods Mol Biol 579:375–389PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Finsterer J (2008) Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). J Neurol Sci 272:20–33PubMedCrossRefGoogle Scholar
  31. 31.
    Claypool SM, Koehler CM (2011) The complexity of cardiolipin in health and disease. Trends Biochem Sci 37:32PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Todorova MT, Mantis JG, Le M, Kim CY, Seyfried TN (2006) Genetic and environmental interactions determine seizure susceptibility in epileptic EL mice. Genes Brain Behav 5:518–527PubMedCrossRefGoogle Scholar
  33. 33.
    Todorova MT, Burwell TJ, Seyfried TN (1999) Environmental risk factors for multifactorial epilepsy in EL mice. Epilepsia 40:1697–1707PubMedCrossRefGoogle Scholar

Copyright information

© AOCS 2013

Authors and Affiliations

  • Nathan L. Ta
    • 1
  • Xibei Jia
    • 1
  • Michael Kiebish
    • 2
  • Thomas N. Seyfried
    • 1
    Email author
  1. 1.Biology DepartmentBoston CollegeChestnut HillUSA
  2. 2.Berg DiagnosticsNatickUSA

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