title: Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia.
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.
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Aza
authors.initials: A
authors.lastname: Shetewy
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Shimada-Takaura
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Warner
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Chian Ju
authors.initials: CJ
authors.lastname: Jong
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Abu-Bakr Al
authors.initials: AB
authors.lastname: Mehdi
authors.affiliation: Department of Cell Biology/Neuroscience, University of South Alabama College of Medicine, Mobile, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Alexeyev
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA. sschaffe@southalabama.edu.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Schaffer
mesh_terms: D000818:Animals; D006970:Disorders of Excessive Somnolence / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption; D051381:Rats; D012640:Seizures / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013654:Taurine / Q000096:biosynthesis / Q000235:genetics; D015091:beta-Alanine / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D015091:beta-Alanine; D013654:Taurine; D042967:Electron Transport Complex I
keywords: Apoptosis; Electron transport chain; Mitochondrial fragmentation; Oxidative stress; Respiration; Taurine