Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1995 Sep 15;310(Pt 3):887–892. doi: 10.1042/bj3100887

Mitochondrial ATP synthase subunit c stored in hereditary ceroid-lipofuscinosis contains trimethyl-lysine.

M L Katz 1, C L Gao 1, J A Tompkins 1, R T Bronson 1, D T Chin 1
PMCID: PMC1135979  PMID: 7575423

Abstract

The subunit c protein of mitochondrial ATP synthase accumulates in lysosomal storage bodies of numerous tissues in human subjects with certain forms of ceroid-lipofuscinosis, a degenerative hereditary disease. Subunit c appears to constitute a major fraction of the total storage-body protein. Lysosomal accumulation of subunit c has also been reported in putative animal models (dogs, sheep and mice) for ceroid-lipofuscinosis. In humans with the juvenile form of the disease, hydrolysates of total storage-body protein have been found to contain significant amounts of epsilon-N-trimethyl-lysine (TML). TML is also abundant in storage-body protein hydrolysates from affected dogs and sheep. These findings suggested that one or both of the two lysine residues of subunit c might be methylated in the stored form of the protein. The normal subunit c protein from mitochondria does not appear to be methylated. In a putative canine model for human juvenile ceroid-lipofuscinosis, residue 43 of the storage-body subunit c was previously found to be TML. In the present study, subunit c was isolated from the storage bodies of humans with juvenile ceroid-lipofuscinosis, and from sheep and mice with apparently analogous diseases. In all three species, partial amino acid sequence analysis of the stored subunit c indicated that the protein contained TML at residue 43. These findings strongly suggest that specific methylation of lysine residue 43 of mitochondrial ATP synthase plays a central role in the lysosomal storage of this protein.

Full text

PDF
887

Images in this article

889Figure 1
on p.889
889Figure 2
on p.889

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bieber L. L. Carnitine. Annu Rev Biochem. 1988;57:261–283. doi: 10.1146/annurev.bi.57.070188.001401. [DOI] [PubMed] [Google Scholar]
  2. Boustany R. M., Alroy J., Kolodny E. H. Clinical classification of neuronal ceroid-lipofuscinosis subtypes. Am J Med Genet Suppl. 1988;5:47–58. doi: 10.1002/ajmg.1320310608. [DOI] [PubMed] [Google Scholar]
  3. Brauer A. W., Oman C. L., Margolies M. N. Use of o-phthalaldehyde to reduce background during automated Edman degradation. Anal Biochem. 1984 Feb;137(1):134–142. doi: 10.1016/0003-2697(84)90359-2. [DOI] [PubMed] [Google Scholar]
  4. Bremer J. Carnitine--metabolism and functions. Physiol Rev. 1983 Oct;63(4):1420–1480. doi: 10.1152/physrev.1983.63.4.1420. [DOI] [PubMed] [Google Scholar]
  5. Bronson R. T., Lake B. D., Cook S., Taylor S., Davisson M. T. Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease). Ann Neurol. 1993 Apr;33(4):381–385. doi: 10.1002/ana.410330408. [DOI] [PubMed] [Google Scholar]
  6. Callen D. F., Doggett N. A., Stallings R. L., Chen L. Z., Whitmore S. A., Lane S. A., Nancarrow J. K., Apostolou S., Thompson A. D., Lapsys N. M. High-resolution cytogenetic-based physical map of human chromosome 16. Genomics. 1992 Aug;13(4):1178–1185. doi: 10.1016/0888-7543(92)90035-q. [DOI] [PubMed] [Google Scholar]
  7. Dyer M. R., Gay N. J., Walker J. E. DNA sequences of a bovine gene and of two related pseudogenes for the proteolipid subunit of mitochondrial ATP synthase. Biochem J. 1989 May 15;260(1):249–258. doi: 10.1042/bj2600249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dyken P. R. Reconsideration of the classification of the neuronal ceroid-lipofuscinoses. Am J Med Genet Suppl. 1988;5:69–84. doi: 10.1002/ajmg.1320310610. [DOI] [PubMed] [Google Scholar]
  9. Ezaki J., Wolfe L. S., Higuti T., Ishidoh K., Kominami E. Specific delay of degradation of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid lipofuscinosis (Batten disease). J Neurochem. 1995 Feb;64(2):733–741. doi: 10.1046/j.1471-4159.1995.64020733.x. [DOI] [PubMed] [Google Scholar]
  10. Faust J. R., Rodman J. S., Daniel P. F., Dice J. F., Bronson R. T. Two related proteolipids and dolichol-linked oligosaccharides accumulate in motor neuron degeneration mice (mnd/mnd), a model for neuronal ceroid lipofuscinosis. J Biol Chem. 1994 Apr 1;269(13):10150–10155. [PubMed] [Google Scholar]
  11. Fearnley I. M., Walker J. E., Martinus R. D., Jolly R. D., Kirkland K. B., Shaw G. J., Palmer D. N. The sequence of the major protein stored in ovine ceroid lipofuscinosis is identical with that of the dicyclohexylcarbodiimide-reactive proteolipid of mitochondrial ATP synthase. Biochem J. 1990 Jun 15;268(3):751–758. doi: 10.1042/bj2680751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goebel H. H., Bilzer T., Dahme E., Malkusch F. Morphological studies in canine (Dalmatian) neuronal ceroid-lipofuscinosis. Am J Med Genet Suppl. 1988;5:127–139. doi: 10.1002/ajmg.1320310617. [DOI] [PubMed] [Google Scholar]
  13. Goebel H. H., Zeman W., Patel V. K., Pullarkat R. K., Lenard H. G. On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis. Mech Ageing Dev. 1979 Apr;10(1-2):53–70. doi: 10.1016/0047-6374(79)90070-8. [DOI] [PubMed] [Google Scholar]
  14. Hall N. A., Lake B. D., Dewji N. N., Patrick A. D. Lysosomal storage of subunit c of mitochondrial ATP synthase in Batten's disease (ceroid-lipofuscinosis). Biochem J. 1991 Apr 1;275(Pt 1):269–272. doi: 10.1042/bj2750269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jolly R. D., Janmaat A., West D. M., Morrison I. Ovine ceroid-lipofuscinosis: a model of Batten's disease. Neuropathol Appl Neurobiol. 1980 May-Jun;6(3):195–209. doi: 10.1111/j.1365-2990.1980.tb00290.x. [DOI] [PubMed] [Google Scholar]
  16. Jolly R. D., Shimada A., Craig A. S., Kirkland K. B., Palmer D. N. Ovine ceroid-lipofuscinosis II: Pathologic changes interpreted in light of biochemical observations. Am J Med Genet Suppl. 1988;5:159–170. doi: 10.1002/ajmg.1320310619. [DOI] [PubMed] [Google Scholar]
  17. Järvelä I., Santavuori P., Puhakka L., Haltia M., Peltonen L. Linkage map of the chromosomal region surrounding the infantile neuronal ceroid lipofuscinosis on 1p. Am J Med Genet. 1992 Feb 15;42(4):546–548. doi: 10.1002/ajmg.1320420425. [DOI] [PubMed] [Google Scholar]
  18. Järvelä I., Schleutker J., Haataja L., Santavuori P., Puhakka L., Manninen T., Palotie A., Sandkuijl L. A., Renlund M., White R. Infantile form of neuronal ceroid lipofuscinosis (CLN1) maps to the short arm of chromosome 1. Genomics. 1991 Jan;9(1):170–173. doi: 10.1016/0888-7543(91)90235-7. [DOI] [PubMed] [Google Scholar]
  19. Järvelä I., Vesa J., Santavuori P., Hellsten E., Peltonen L. Molecular genetics of neuronal ceroid lipofuscinoses. Pediatr Res. 1992 Dec;32(6):645–648. doi: 10.1203/00006450-199212000-00003. [DOI] [PubMed] [Google Scholar]
  20. Katz M. L., Christianson J. S., Norbury N. E., Gao C. L., Siakotos A. N., Koppang N. Lysine methylation of mitochondrial ATP synthase subunit c stored in tissues of dogs with hereditary ceroid lipofuscinosis. J Biol Chem. 1994 Apr 1;269(13):9906–9911. [PubMed] [Google Scholar]
  21. Katz M. L., Gerhardt K. O. Methylated lysine in storage body protein of sheep with hereditary ceroid-lipofuscinosis. Biochim Biophys Acta. 1992 Feb 14;1138(2):97–108. doi: 10.1016/0925-4439(92)90048-r. [DOI] [PubMed] [Google Scholar]
  22. Katz M. L., Gerhardt K. O. Storage protein in hereditary ceroid-lipofuscinosis contains S-methylated methionine. Mech Ageing Dev. 1990 Apr 30;53(3):277–290. doi: 10.1016/0047-6374(90)90045-h. [DOI] [PubMed] [Google Scholar]
  23. Katz M. L., Robison W. G., Jr Age-related changes in the retinal pigment epithelium of pigmented rats. Exp Eye Res. 1984 Feb;38(2):137–151. doi: 10.1016/0014-4835(84)90098-8. [DOI] [PubMed] [Google Scholar]
  24. Katz M. L., Robison W. G., Jr Evidence of cell loss from the rat retina during senescence. Exp Eye Res. 1986 Apr;42(4):293–304. doi: 10.1016/0014-4835(86)90022-9. [DOI] [PubMed] [Google Scholar]
  25. Katz M. L., Rodrigues M. Juvenile ceroid lipofuscinosis. Evidence for methylated lysine in neural storage body protein. Am J Pathol. 1991 Feb;138(2):323–332. [PMC free article] [PubMed] [Google Scholar]
  26. Katz M. L., Siakotos A. N. Canine hereditary ceroid-lipofuscinosis: evidence for a defect in the carnitine biosynthetic pathway. Am J Med Genet. 1995 Jun 5;57(2):266–271. doi: 10.1002/ajmg.1320570231. [DOI] [PubMed] [Google Scholar]
  27. Koppang N. The English setter with ceroid-lipofuscinosis: a suitable model for the juvenile type of ceroid-lipofuscinosis in humans. Am J Med Genet Suppl. 1988;5:117–125. doi: 10.1002/ajmg.1320310616. [DOI] [PubMed] [Google Scholar]
  28. LaBadie J., Dunn W. A., Aronson N. N., Jr Hepatic synthesis of carnitine from protein-bound trimethyl-lysine. Lysosomal digestion of methyl-lysine-labelled asialo-fetuin. Biochem J. 1976 Oct 15;160(1):85–95. doi: 10.1042/bj1600085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lerner T. J., Boustany R. M., MacCormack K., Gleitsman J., Schlumpf K., Breakefield X. O., Gusella J. F., Haines J. L. Linkage disequilibrium between the juvenile neuronal ceroid lipofuscinosis gene and marker loci on chromosome 16p 12.1. Am J Hum Genet. 1994 Jan;54(1):88–94. [PMC free article] [PubMed] [Google Scholar]
  30. Medd S. M., Walker J. E., Jolly R. D. Characterization of the expressed genes for subunit c of mitochondrial ATP synthase in sheep with ceroid lipofuscinosis. Biochem J. 1993 Jul 1;293(Pt 1):65–73. doi: 10.1042/bj2930065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mitchison H. M., O'Rawe A. M., Lerner T. J., Taschner P. E., Schlumpf K., D'Arigo K., de Vos N., Gormally E., Phillips H. A., Thompson A. D. Refined localization of the Batten disease gene (CLN3) by haplotype and linkage disequilibrium mapping to D16S288-D16S383 and exclusion from this region of a variant form of Batten disease with granular osmiophilic deposits. Am J Med Genet. 1995 Jun 5;57(2):312–315. doi: 10.1002/ajmg.1320570241. [DOI] [PubMed] [Google Scholar]
  32. Mitchison H. M., Thompson A. D., Mulley J. C., Kozman H. M., Richards R. I., Callen D. F., Stallings R. L., Doggett N. A., Attwood J., McKay T. R. Fine genetic mapping of the Batten disease locus (CLN3) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci. Genomics. 1993 May;16(2):455–460. doi: 10.1006/geno.1993.1210. [DOI] [PubMed] [Google Scholar]
  33. Palmer D. N., Bayliss S. L., Clifton P. A., Grant V. J. Storage bodies in the ceroid-lipofuscinoses (Batten disease): low-molecular-weight components, unusual amino acids and reconstitution of fluorescent bodies from non-fluorescent components. J Inherit Metab Dis. 1993;16(2):292–295. doi: 10.1007/BF00710268. [DOI] [PubMed] [Google Scholar]
  34. Palmer D. N., Fearnley I. M., Walker J. E., Hall N. A., Lake B. D., Wolfe L. S., Haltia M., Martinus R. D., Jolly R. D. Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease). Am J Med Genet. 1992 Feb 15;42(4):561–567. doi: 10.1002/ajmg.1320420428. [DOI] [PubMed] [Google Scholar]
  35. Palmer D. N., Martinus R. D., Barns G., Reeves R. D., Jolly R. D. Ovine ceroid-lipofuscinosis. I: Lipopigment composition is indicative of a lysosomal proteinosis. Am J Med Genet Suppl. 1988;5:141–158. doi: 10.1002/ajmg.1320310618. [DOI] [PubMed] [Google Scholar]
  36. Palmer D. N., Martinus R. D., Cooper S. M., Midwinter G. G., Reid J. C., Jolly R. D. Ovine ceroid lipofuscinosis. The major lipopigment protein and the lipid-binding subunit of mitochondrial ATP synthase have the same NH2-terminal sequence. J Biol Chem. 1989 Apr 5;264(10):5736–5740. [PubMed] [Google Scholar]
  37. Rebouche C. J. Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr. 1991 Dec;54(6 Suppl):1147S–1152S. doi: 10.1093/ajcn/54.6.1147s. [DOI] [PubMed] [Google Scholar]
  38. Stanley C. A., Hale D. E., Berry G. T., Deleeuw S., Boxer J., Bonnefont J. P. Brief report: a deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane. N Engl J Med. 1992 Jul 2;327(1):19–23. doi: 10.1056/NEJM199207023270104. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES