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

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Abstract

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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Acknowledgments

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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Authors and Affiliations

  1. Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA

    Aza Shetewy, Kayoko Shimada-Takaura, Danielle Warner, Chian Ju Jong, Abu-Bakr Al Mehdi & Stephen W. Schaffer

  2. Department of Cell Biology/Neuroscience, University of South Alabama College of Medicine, Mobile, USA

    Mikhail Alexeyev

  3. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    Kyoko Takahashi

Authors
  1. Aza Shetewy
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  2. Kayoko Shimada-Takaura
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  3. Danielle Warner
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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). https://doi.org/10.1007/s11010-016-2688-z

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  • DOI: https://doi.org/10.1007/s11010-016-2688-z

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