Skip to main content
SpringerLink
Log in

Brain Mitochondrial Lipid Abnormalities in Mice Susceptible to Spontaneous Gliomas

  • Original Article
  • Published:
Lipids

Abstract

Alterations in mitochondrial function have long been considered a hallmark of cancer. We compared the lipidome and electron transport chain activities of non-synaptic brain mitochondria in two inbred mouse strains, the C57BL/6J (B6) and the VM/Dk (VM). The VM strain is unique in expressing a high incidence of spontaneous brain tumors (1.5%) that are mostly gliomas. The incidence of gliomas is about 210-fold greater in VM mice than in B6 mice. Using shotgun lipidomics, we found that the mitochondrial content of ethanolamine glycerophospholipid, phosphatidylserine, and ceramide was higher, whereas the content of total choline glycerophospholipid was lower in the VM mice than in B6 mice. Total cardiolipin content was similar in the VM and the B6 mice, but the distribution of cardiolipin molecular species differed markedly between the strains. B6 non-synaptic mitochondria contained 95 molecular species of cardiolipin that were symmetrically distributed over 7 major groups based on mass charge. In contrast, VM non-synaptic mitochondria contained only 42 molecular species that were distributed asymmetrically. The activities of Complex I, I/III, and II/III enzymes were lower, whereas the activity of complex IV was higher in the mitochondria of VM mice than in B6 mice. The high glioma incidence and alterations in electron transport chain activities in VM mice compared to B6 mice could be related to the unusual composition of mitochondrial lipids in the VM mouse brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1
Fig 2
Fig 3

Similar content being viewed by others

References

  1. Bowling AC, Beal MF (1995) Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci 56:1151–1171

    Article  PubMed  CAS  Google Scholar 

  2. Calabrese V, Scapagnini G, Giuffrida Stella AM, Bates TE, Clark JB (2001) Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochem Res 26:739–764

    Article  PubMed  CAS  Google Scholar 

  3. Pope S, Land JM, Heales SJ (2008) Oxidative stress and mitochondrial dysfunction in neurodegeneration: cardiolipin a critical target? Biochim Biophys Acta. doi:10.1016/j.bbabio.2008.030011

  4. Daum G (1985) Lipids of mitochondria. Biochim Biophys Acta 822:1–42

    PubMed  CAS  Google Scholar 

  5. Hoch FL (1992) Cardiolipins and biomembrane function. Biochim Biophys Acta 1113:71–133

    PubMed  CAS  Google Scholar 

  6. Petrushka E, Quastel JH, Scholefield PG (1959) Role of phospholipids in oxidative phosphorylation and mitochondrial structure. Can J Biochem Physiol 37:989–998

    PubMed  CAS  Google Scholar 

  7. Shinzawa-Itoh K, Aoyama H, Muramoto K, Terada H, Kurauchi T, Tadehara Y, Yamasaki A, Sugimura T, Kurono S, Tsujimoto K, Mizushima T, Yamashita E, Tsukihara T, Yoshikawa S (2007) Structures and physiological roles of 13 integral lipids of bovine heart cytochrome c oxidase. EMBO J 26:1713–1725

    Article  PubMed  CAS  Google Scholar 

  8. Jiang F, Ryan MT, Schlame M, Zhao M, Gu Z, Klingenberg M, Pfanner N, Greenberg ML (2000) Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function. J Biol Chem 275:22387–22394

    Article  PubMed  CAS  Google Scholar 

  9. Davey GP, Clark JB (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem 66:1617–1624

    Article  PubMed  CAS  Google Scholar 

  10. Han X, Gross RW (2005) Shotgun lipidomics: multidimensional MS analysis of cellular lipidomes. Expert Rev Proteomics 2:253–264

    Article  PubMed  CAS  Google Scholar 

  11. 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/6J mouse brain mitochondria. J Neurochem. doi:10.1111/j.1471-4159.2008.05383.x

  12. 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 47:5869–5880

    Article  PubMed  CAS  Google Scholar 

  13. Bedell MA, Jenkins NA, Copeland NG (1997) Mouse models of human disease. Part I: techniques and resources for genetic analysis in mice. Genes Dev 11:1–10

    Article  PubMed  CAS  Google Scholar 

  14. Bedell MA, Largaespada DA, Jenkins NA, Copeland NG (1997) Mouse models of human disease. Part II: recent progress and future directions. Genes Dev 11:11–43

    Article  PubMed  Google Scholar 

  15. Fraser H (1971) Astrocytomas in an inbred mouse strain. J Pathol 103:266–270

    Article  PubMed  CAS  Google Scholar 

  16. Huysentruyt LC, Mukherjee P, Banerjee D, Shelton LM, Seyfried TN (2008) Metastatic cancer cells with macrophage properties: Evidence from a new murine tumor model. Int J Cancer 123:73–84

    Article  PubMed  CAS  Google Scholar 

  17. Fraser H (1986) Brain tumours in mice, with particular reference to astrocytoma. Food Chem Toxicol 24:105–111

    Article  PubMed  CAS  Google Scholar 

  18. Warburg O (1931) The metabolism of tumours. Richard R. Smith Inc, New York

    Google Scholar 

  19. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  PubMed  CAS  Google Scholar 

  20. Cavalli LR, Liang BC (1998) Mutagenesis, tumorigenicity, and apoptosis: are the mitochondria involved? Mutat Res 398:19–26

    PubMed  CAS  Google Scholar 

  21. Augenlicht LH, Heerdt BG (2001) Mitochondria: integrators in tumorigenesis? Nat Genet 28:104–105

    Article  PubMed  CAS  Google Scholar 

  22. Lai JC, Clark JB (1976) Preparation and properties of mitochondria derived from synaptosomes. Biochem J 154:423–432

    PubMed  CAS  Google Scholar 

  23. Lai JC, Walsh JM, Dennis SC, Clark JB (1977) Synaptic and non-synaptic mitochondria from rat brain: isolation and characterization. J Neurochem 28:625–631

    Article  PubMed  CAS  Google Scholar 

  24. Mena EE, Hoeser CA, Moore BW (1980) An improved method of preparing rat brain synaptic membranes. Elimination of a contaminating membrane containing 2′, 3′-cyclic nucleotide 3′-phosphohydrolase activity. Brain Res 188:207–231

    Article  PubMed  CAS  Google Scholar 

  25. Dagani F, Gorini A, Polgatti M, Villa RF, Benzi G (1983) Synaptic and non-synaptic mitochondria from rat cerebral cortex. Characterization and effect of pharmacological treatment on some enzyme activities related to energy transduction. Farmaco (Sci) 38:584–594

    CAS  Google Scholar 

  26. Rendon A, Masmoudi A (1985) Purification of non-synaptic and synaptic mitochondria and plasma membranes from rat brain by a rapid Percoll gradient procedure. J Neurosci Methods 14:41–51

    Article  PubMed  CAS  Google Scholar 

  27. Battino M, Bertoli E, Formiggini G, Sassi S, Gorini A, Villa RF, Lenaz G (1991) Structural and functional aspects of the respiratory chain of synaptic and nonsynaptic mitochondria derived from selected brain regions. J Bioenerg Biomembr 23:345–363

    Article  PubMed  CAS  Google Scholar 

  28. Brown MR, Sullivan PG, Geddes JW (2006) Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem 281:11658–11668

    Article  PubMed  CAS  Google Scholar 

  29. Cheng H, Guan S, Han X (2006) Abundance of triacylglycerols in ganglia and their depletion in diabetic mice: implications for the role of altered triacylglycerols in diabetic neuropathy. J Neurochem 97:1288–1300

    Article  PubMed  CAS  Google Scholar 

  30. Han X, Yang J, Cheng H, Ye H, Gross RW (2004) Toward fingerprinting cellular lipidomes directly from biological samples by two-dimensional electrospray ionization mass spectrometry. Anal Biochem 330:317–331

    Article  PubMed  CAS  Google Scholar 

  31. Birch-Machin MA, Turnbull DM (2001) Assaying mitochondrial respiratory complex activity in mitochondria isolated from human cells and tissues. Methods Cell Biol 65:97–117

    Article  PubMed  CAS  Google Scholar 

  32. Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barcelo-Coblijn GC, Nussbaum RL (2005) Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein. Mol Cell Biol 25:10190–10201

    Article  PubMed  CAS  Google Scholar 

  33. King TE (1967) Preparation of succinate dehydrogenase and reconstitution of succinate oxidase. In: Estabrook RW, Pullman ME (eds) Methods enzymol. Academic Press, New York, pp 322–331

    Google Scholar 

  34. Degli Esposti M (2001) Assessing functional integrity of mitochondria in vitro and in vivo. Methods Cell Biol 65:75–96

    Article  PubMed  CAS  Google Scholar 

  35. Yonetan T (1967) Cytochrome oxidase: beef heart. In: Estabrook RW, Pullman ME (eds) Methods enzymol. Academic Press, New York pp, 332–335

    Google Scholar 

  36. Bangur CS, Howland JL, Katyare SS (1995) Thyroid hormone treatment alters phospholipid composition and membrane fluidity of rat brain mitochondria. Biochem J 305(Pt 1):29–32

    PubMed  CAS  Google Scholar 

  37. Brand MD, Turner N, Ocloo A, Else PL, Hulbert AJ (2003) Proton conductance and fatty acyl composition of liver mitochondria correlates with body mass in birds. Biochem J 376:741–748

    Article  PubMed  CAS  Google Scholar 

  38. Fleischer S, Brierley G, Klouwen H, Slautterback DB (1962) Studies of the electron transfer system. 47. The role of phospholipids in electron transfer. J Biol Chem 237:3264–3272

    PubMed  CAS  Google Scholar 

  39. Schlame M, Ren M, Xu Y, Greenberg ML, Haller I (2005) Molecular symmetry in mitochondrial cardiolipins. Chem Phys lipids 138:38–49

    Article  PubMed  CAS  Google Scholar 

  40. Schlame M (2007) Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. J Lipid Res. doi:10.1194/JLR.R700018JLR200

  41. Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292:C33–C44

    Article  PubMed  CAS  Google Scholar 

  42. Fry M, Green DE (1981) Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain. J Biol Chem 256:1874–1880

    PubMed  CAS  Google Scholar 

  43. Pfeiffer K, Gohil V, Stuart RA, Hunte C, Brandt U, Greenberg ML, Schagger H (2003) Cardiolipin stabilizes respiratory chain supercomplexes. J Biol Chem 278:52873–52880

    Article  PubMed  CAS  Google Scholar 

  44. Zhang M, Mileykovskaya E, Dowhan W (2002) Gluing the respiratory chain together. Cardiolipin is required for supercomplex formation in the inner mitochondrial membrane. J Biol Chem 277:43553–43556

    Article  PubMed  CAS  Google Scholar 

  45. McKenzie M, Lazarou M, Thorburn DR, Ryan MT (2006) Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol 361:462–469

    Article  PubMed  CAS  Google Scholar 

  46. Kraffe E, Soudant P, Marty Y, Kervarec N, Jehan P (2002) Evidence of a tetradocosahexaenoic cardiolipin in some marine bivalves. Lipids 37:507–514

    Article  PubMed  CAS  Google Scholar 

  47. Yamaoka S, Urade R, Kito M (1988) Mitochondrial function in rats is affected by modification of membrane phospholipids with dietary sardine oil. J Nutr 118:290–296

    PubMed  CAS  Google Scholar 

  48. Fry M, Blondin GA, Green DE (1980) The localization of tightly bound cardiolipin in cytochrome oxidase. J Biol Chem 255:9967–9970

    PubMed  CAS  Google Scholar 

  49. Gohil VM, Hayes P, Matsuyama S, Schagger H, Schlame M, Greenberg ML (2004) Cardiolipin biosynthesis and mitochondrial respiratory chain function are interdependent. J Biol Chem 279:42612–42618

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Purna Mukherjee, Rena Baek, and John Mantis for helpful discussions. This work was supported by grants from NIH (HD39722), NCI (CA102135), and NIA (AG23168).

Author information

Authors and Affiliations

  1. Biology Department, Boston College, Chestnut Hill, MA, USA

    Michael A. Kiebish, Jeffrey H. Chuang & Thomas N. Seyfried

  2. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA

    Xianlin Han & Hua Cheng

Authors
  1. Michael A. Kiebish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xianlin Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hua Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey H. Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas N. Seyfried
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas N. Seyfried.

Electronic supplementary material

Below is the link to the electronic supplementary material.

MOESM1 (DOC 108 kb)

About this article

Cite this article

Kiebish, M.A., Han, X., Cheng, H. et al. Brain Mitochondrial Lipid Abnormalities in Mice Susceptible to Spontaneous Gliomas. Lipids 43, 951–959 (2008). https://doi.org/10.1007/s11745-008-3197-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-008-3197-y

Keywords

Search

Navigation