Skip to main content
SpringerLink
Log in

Metabolic interventions against complex I deficiency in MELAS syndrome

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Diseases caused by mtDNA defects are manifested as variable clinical phenotypes and the symptoms represent the involvement of tissues with high energy demand. Various approaches have been taken to treat mitochondrial diseases by administration of redox compounds, enzyme activators, vitamins and coenzymes or dietary measures.

The MELAS mutation at the base pair 3243 of mitochondrial DNA demolishes a transcription termination sequence located within the tRNALeu[UUR] gene, resulting in synthesis of an abnormally large derivative of 16 S rRNA and defective translation. The activity of NADH:Q oxidoreductase (complex I) is often decreased and lactic acidosis is a typical clinical finding.

We hypothesized that defective translation of the seven mitochondrially coded subunits (of the total 41) of complex I may alter its affinity to the NADH substrate in which case the activity decrease may be compensated for by increasing the NADH concentration.

A MELAS patient was treated with oral nicotinamide for 5 months. The blood NAD content representing the NAD + NADH pool of erythrocytes rose 24 fold and the blood lactate + pyrovate concentration fell by 50%.

All these metabolic alterations suggested an improvement of the function of complex I or the whole mitochondrial respiratory chain. However, the kinetic properties of the patient's complex I were similar to the reference values. A tempting explanation is that the free NADH concentration in mitochondria is normally at the level of Km, so that the decreased activity of the respiratory chain can be compensated for by increased mitochondrial [NADH]. Another possibility would be that the substrate shuttles for transport of reducing power of cytosolic NADH into mitochondria (the malate aspartate or glycerol-3-phosphate shuttles) may be enhanced by increased total NAD + NADH. Because the malate-aspartate shuttle is actually a pump for reducing equivalents driven by the mitochondrial membrane energization, it is proposed that the exacerbations of the MELAS syndrome be partly due to a vicious circle initiated by a defect of complex I and affecting the active transport of the hydrogen from cytos olic NADH into the mitochondrion. (Mol Cell Biochem 174: 291–296, 1997)

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

Similar content being viewed by others

References

  1. Saijo T, Naito E, Ito M, Takeda E, Hashimoto T, Kuroda Y: Therapeutic effect of sodium dichloroacetate on visual and auditory hallucinations in a patient with MELAS. Neuropediatrics 22: 166–197, 1991

    Google Scholar 

  2. Stackpoole PW, Harman EM, Baumgartner TG, Misbin RI: Treatment of lactic acidosis with dichloroacetate. N Engl J Med 309: 390–396, 1983

    Google Scholar 

  3. Arts WFM, Scholte HR, Boggard JM, Kerrebijn KF, Luyt-Houwen IEM: NADH-CoQ reductase deficient myopathy: successful treatment with riboflavin. Lancet 2: 581–582, 1983

    Google Scholar 

  4. Ihara Y, Namba R, Kuroda S, Sato T, Shirabe T: Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme O2 and idebenone. J Neurol Sci 90: 263–271, 1989

    Google Scholar 

  5. Penn AMW, Lee JWK, Thuilier P, Wagner M, Maclure KM, Menard MR, Hall LD, Kennaway NG: MELAS syndrome with mitochondrial tRNALeu[UUR] mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 42: 2147–2152, 1992

    Google Scholar 

  6. Zierz S, von Wersebe O, Bleistein J, Jerusalem F: Exogeous coenzyme Q (CoQ) fails to increase CoQ in skeletal muscle of 2 patients with mitochondrial myopathies. J Neurol Sci 95: 283–290, 1990

    Google Scholar 

  7. Mathews PM, Ford B, Dandurand RJ, Eidelman DH, O'Connor D, Shervin A, Karpati G, Anderman F, Arnold DL: Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 43: 884–890, 1993

    Google Scholar 

  8. Eleff S, Kennaway NG, Buist NRM, Darley-Usmar VM, Capaldi RA, Bank WJ, Chance B: 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc Nat Acad Sci USA 81: 3529–3533, 19??

  9. Thor H, Smith MT, Harzell P, Belomo G, Jewell SA, Orrenius S: The metabolism of menadione (2-methyl-1,4,-naphtoquinine) by isolated hepatocytes. J Biol Chem 257: 12419–12425, 1982

    Google Scholar 

  10. Maellaro E, Del Bello B, Sugherini L, Pompella A, Casini AF, Comporti M: Protection by ascorbic acid against oxidative injury of isolated hepatocytes. Xenobiotica 24: 281–289, 1994

    Google Scholar 

  11. Bernsen PLJA, Gabreëls FJM, Ruitenbeek W, Sengers RCA, Stadhouders AM, Renier WO: Successful treatment of pure myopathy, associated with complex I deficiency, with riboflavin and carnitine. Arch Neurol 48: 334–338, 1991

    Google Scholar 

  12. Bernsen PL, Gabreëls FJ, Ruitenbeek W, Hamburger HL: Treatment of complex I deficiency with riboflavin. J Neurol Sci 118: 181–187, 1993

    Google Scholar 

  13. Ishiki T, Tanaka M, Nishikimi M et al.: Deficiency of subunits of complex I and mitochondrial encephalomyopathy. Ann Neurol 23: 287–294, 1988

    Google Scholar 

  14. Kaplan NO, Goldin A, Humphreys SR, Ciotti MM, Stolzenbach FE: Pyridine nucleotide synthesis in the mouse. J Biol Chem 219: 287–292, 1956

    Google Scholar 

  15. Eriksson CPJ: Increase in hepatic NAD level – its effect on the redox state and on ethanol and acetaldehyde metabolism. FEBS Lett 40: 317–320, 1974

    Google Scholar 

  16. King MP, Koga Y, Davidson M, Schon EA.: Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu[UUR] mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Mol Cell Biol 12: 480–490, 1992

    Google Scholar 

  17. van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, van de Kamp JJ, Maassen JA: Mutation in mitochondrial tRNA Leu[UUR] gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1: 368–371, 1992

    Google Scholar 

  18. van den Ouweland JM, Lemkes HH, Trembath RC, Ross R, Velho G, Cohen D, Froguel P, Maassen JA: Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA Leu[UUR] gene. Diabetes 43: 746–751, 1994

    Google Scholar 

  19. Remes AM, Majamaa K, Herva R, Hassinen IE: Adult-onset diabetes mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with the tRNA Leu[UUR] mutation. Neurology 43: 1015–1020, 1993

    Google Scholar 

  20. Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda F, Kasuga M: Diabetes mellitus carrying a mutation in the mitochondrial tRNALeu[UUR] cene. Diabetologia 38: 193–200, 1995

    Google Scholar 

  21. Rötig A, Cormier V, Chatelain P, Francois R, Saudubray JM, Rustin P, Munnich A: Deletion of mitochondrial DNA in a case of earlyonset diabetes mellitus, optic atrophy and deafness (DIDMOAD, Wolfram syndrome). J Inherit Metab Dis 16: 527–530, 1993

    Google Scholar 

  22. Ohta M, Nelson D, Nelson J, Meglasson MD, Erecinska M: Relationship between energy level and insulin secretion in isolated rat islets of Langerhans. Biochem Pharmacol 42: 593–598, 1991

    Google Scholar 

  23. Earley FGP, Patel SD, Ragan CI, Attardi G: Photolabeling of a mitochondrially encoded subunit of NADH dehydrogenase with [3H]dihydrorotenone. FEBS Lett 219: 108–113, 1987

    Google Scholar 

  24. Borst P: Hydrogen transport and transport metabolites. In: Funktionelle und Morphologische Organisation der Zelle, Wissenschaftliche Konferenz der Gesellschaft deutscher Naturforscher und Ärzte, Rottach-Egern, Springer-Verlag, Würzburg, 1962, pp 137–158

    Google Scholar 

  25. Hassinen IE: Mitochondrial respiratory control in the myocardium. Biochim Biophys Acta 853: 135–151, 1986

    Google Scholar 

  26. Bücher T, Brauser B, Conze A, Klein F, Langguth O, Sies H: State of oxidation-reduction and state of binding in the cytosolic NADH system as disclosed by equilibration with extracellular lactate/pyrovate in hemoglobin-free perfused rat liver. Eur J Biochem 27: 301––317, 1972

    Google Scholar 

  27. Nuutinen EM: Subcellular origin of the surface fluorescence of reduced nicotinamide nucleotides in the isolated perfused rat heart. Basic Res Cardiol 79: 49–59, 1984

    Google Scholar 

  28. Majamaa K, Rusanen H, Remes AM, Pyhtinen J, Hassinen IE: Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. Life Sci 58: 691–699, 1996

    Google Scholar 

  29. Makinen MW, Lee CP: Biochemical studies of muscle mitochondria. I. Microanalysis of cytochrome content, oxidative and phosphorylative activities of mammalian skeletal muscle mitochondria. Arch Biochem Biophys 126: 75–82, 1968

    Google Scholar 

  30. Zheng X, Schoffner JM, Voljavec AS, Wallace DC: Evaluation of procedures for assaying oxidative phosphorylation enzyme activities in mitochondrial myopathy muscle biopsies. Biochim Biophys Acta 1019: 1–10, 1990

    Google Scholar 

  31. Yun S-L, Suelter CH: Simple method for calculating Km and V from a single enzyme reaction progress curve. Biochim Biophys Acta 480: 1–13, 1977

    Google Scholar 

  32. Klingenberg M: In: HU Bergmeyer (ed). Methods of Enzymatic Analysis. Academic Press, New York, 1963, pp 528–530

    Google Scholar 

  33. Lowry OH, Passonneau JV: A Flexible System of Enzymatic Analysis, Academic Press, New York, 1972, pp 136–139

    Google Scholar 

  34. Kauppinen RA, Hiltunen JK, Hassinen IE: Mitochondrial membrane potential, transmembrane difference in the NAD+ redox potential and the equilibrium of the glutamate-aspartate translocase in the isolated perfused rat heart. Biochim Biophys Acta 725: 425–433, 1983

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, University of Oulu, Oulu, Finland

    Kari Majamaa & Anne Remes

  2. Department of Medical Biochemistry, University of Oulu, Oulu, Finland

    Harri Rusanen & Ilmo E. Hassinen

Authors
  1. Kari Majamaa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harri Rusanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anne Remes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilmo E. Hassinen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Majamaa, K., Rusanen, H., Remes, A. et al. Metabolic interventions against complex I deficiency in MELAS syndrome. Mol Cell Biochem 174, 291–296 (1997). https://doi.org/10.1023/A:1006833200371

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006833200371

Search

Navigation