Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia


Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary β-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that β-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing β-alanine. β-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in β-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that β-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as β-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, β-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that β-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.

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  1. 1.

    Wu FS, Gibbs TT, Farb DH (1993) Dual activation of GABAA and glycine receptors by beta-alanine inverse modulation by progesterone and 5 alpha-pregnan-3 alpha-ol-20-one. Eur J Pharmacol 246:239–246

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Tiedje KE, Stevens K, Barnes S, Weaver DF (2010) β-alanine as a small molecule neurotransmitter. Neurochem Int 57:177–188

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hayaishi O, Nishizuka Y, Tatibana M, Takeshita M, Kuno S (1961) Enzymatic studies on the metabolism of β-alanine. J Biol Chem 236:781–790

    CAS  PubMed  Google Scholar 

  4. 4.

    Derave W, Everaert I, Beeckman S, Baguet A (2010) Muscle carnosine metabolism and β-alanine supplementation in relation to exercise and training. Sports Med 40:247–263

    Article  PubMed  Google Scholar 

  5. 5.

    Yamada EW, Jakoby WB (1960) Aldehyde oxidation. V. Direct conversion of malonic semialdehyde to acetyl-coenzyme A. J Biol Chem 235:589–594

    CAS  PubMed  Google Scholar 

  6. 6.

    Gibson MK, Jakobs C (2001) Disorder of β- and γ-amino acids in free and peptide-linked forms. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw Hill, New York, pp 2079–2105

    Google Scholar 

  7. 7.

    Slavik M, Blanc O, Smith KJ, Slavik J (1983) 6-azauridine triacetate induced hyper beta-alaninemia and its decrease by administration of pyridoxine. J Nutr Sci Vitaminol (Tokyo) 29:631–635

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Kurozumi Y, Abe T, Yao WB, Ubuka T (1999) Experimental beta-alaninuria induced by (aminooxy)acetate. Acta Med Okayama 53:13–18

    CAS  PubMed  Google Scholar 

  9. 9.

    Gemelli T, de Andrade RB, Rojas DB, Bonorino NF, Mazzola PN, Tortorelli LS, Filho CSD, Wannmacher CMD (2013) Mol Cell Biochem 380:161–170

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Schaffer SW, Shimada-Takaura K, Jong CJ, Ito T, Takahashi K (2016) Impaired energy metabolism of the taurine-deficient heart. Amino Acids 7:1–10

    Google Scholar 

  11. 11.

    Grishko V, Pastukh V, Solodushko V, Gillespie M, Azuma J, Schaffer S (2003) Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage. Am J Physiol 285:H2364–H2372

    CAS  Google Scholar 

  12. 12.

    Kussmaul L, Hirst J (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci USA 103(20):7607–7612

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Muller FL, Liu Y, van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279(47):49064–49073

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Ahmad T, Aggarwal K, Pattnaik B, Mukherjee S, Sethi T, Tiwari BK, Kumar M, Micheal A, Mabalirajan U, Ghosh B, Roy SS, Aggarwal A (2013) Computational classification of mitochondrial shapes reflects stress and redox state. Cell Death Dis 4:1–10

    Article  Google Scholar 

  15. 15.

    Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators fis1, drp1 and opa1 in apoptosis. Mol Biol Cell 15:5001–5011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Caruso J, Charles J, Unruh K, Giebel R, Learmonth L, Potter W (2012) Ergogenic effects of β-alanine and carnosine: proposed future research to quantify their efficacy. Nutrients 4:586–601

    Article  Google Scholar 

  17. 17.

    Jong CJ, Ito T, Mozaffari M, Azuma J, Schaffer S (2010) Effects of β-alanine treatment on mitochondrial taurine level and 5-taurinomethyluridine content. J Biomed Sci 17(S1):525–532

    Google Scholar 

  18. 18.

    Jong CJ, Azuma J, Schaffer S (2012) Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production. Amino Acids 42(6):2223–2232

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Schaffer SW, Jong CJ, Ito T, Azuma J (2014) Role of taurine in the pathologies of MELAS and MERRF. Amino Acids 46(1):47–56

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Kirino Y, Goto Y, Campos Y, Arenas J, Suzuki T (2005) Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. Proc Natl Acad Sci USA 102:7127–7132

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Turrens J, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191:421–427

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wu CC, Bratton SB (2013) Regulation of the intrinsic apoptosis pathway by reactive oxygen species. Antioxid Redox Signal 19(6):546–558

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11(9):621–632

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    D’Alessio M, De Nicola M, Coppola S, Gualandi G, Pugliese L, Cerella C, Cristofanon S, Civtareale P, Ciriolo MR, Bergamaschi A, Magrini A, Ghibelli L (2005) Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. FASEB J 19:1504–1506

    PubMed  Google Scholar 

  25. 25.

    Matsuzawa A, Ichijo H (2008) Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim Biophys Acta 1780(11):1325–1336

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Leboucher GP, Tsai YC, Yang M, Shaw KC, Zhou M, Veenstra TD, Glickman MH, Weissman AM (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptoSsis. Mol Cell 47(4):547–557

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Schaffer S, Solodushko V, Pastukh V, Ricci C, Azuma J (2003) Possible cause of taurine deficient cardiomyopathy: potentiation of angiotensin II action. J Cardiovasc Pharmacol 41(5):751–759

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Ramila KC, Jong CJ, Pastukh V, Ito T, Azuma J, Schaffer SW (2015) Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts. Am J Physiol 308(3):H232–H239

    CAS  Google Scholar 

  29. 29.

    Doenst T, Nguyen TD, Abel ED (2013) Heart failure compendium: cardiac metabolism and heart failure: implications beyond ATP production. Circ Res 113:709–724

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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We appreciate the financial support of Taisho Pharmaceutical Co. and the intellectual input of our deceased colleague, Dr. Junichi Azuma, Osaka, Japan.

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Correspondence to Stephen W. Schaffer.

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Shetewy, A., Shimada-Takaura, K., Warner, D. et al. Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia. Mol Cell Biochem 416, 11–22 (2016).

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  • Electron transport chain
  • Oxidative stress
  • Respiration
  • Taurine
  • Mitochondrial fragmentation
  • Apoptosis