Glycine Intracerebroventricular Administration Disrupts Mitochondrial Energy Homeostasis in Cerebral Cortex and Striatum
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ORIGINAL ARTICLE
Glycine Intracerebroventricular Administration Disrupts Mitochondrial Energy Homeostasis in Cerebral Cortex and Striatum of Young Rats Alana Pimentel Moura • Mateus Grings • Belisa dos Santos Parmeggiani • Gustavo Flora Marcowich • Anelise Miotti Tonin • Carolina Maso Viegas • ˆ ngela Zanatta • Ce´sar Augusto Joa˜o Ribeiro • Moacir Wajner • Guilhian Leipnitz A
Received: 4 March 2013 / Revised: 17 April 2013 / Accepted: 23 April 2013 Ó Springer Science+Business Media New York 2013
Abstract High tissue levels of glycine (GLY) are the biochemical hallmark of nonketotic hyperglycinemia (NKH), an inherited metabolic disease clinically characterized by severe neurological symptoms and brain abnormalities. Considering that the mechanisms underlying the neuropathology of this disease are not fully established, the present work investigated the in vivo effects of intracerebroventricular administration of GLY on important parameters of energy metabolism in cerebral cortex and striatum from young rats. Our results show that GLY reduced CO2 production using glucose as substrate and inhibited the activities of citrate synthase and isocitrate dehydrogenase in striatum, whereas no alterations of these parameters were verified in cerebral cortex 30 min after GLY injection. We also observed that GLY diminished the activities of complex IV in cerebral cortex and complex I–III in striatum at 30 min and inhibited complex I–III activity in striatum at 24 h after its injection. Furthermore, GLY reduced the activity of total and mitochondrial creatine kinase in both brain structures 30 min and 24 h after its administration. In contrast, the activity of Na?, K?-ATPase was not altered by GLY. Finally, the antioxidants N-acetylcysteine and creatine, and the NMDA receptor antagonist MK-801 attenuated or fully
A. P. Moura M. Grings B. dos Santos Parmeggiani ˆ . Zanatta G. F. Marcowich A. M. Tonin C. M. Viegas A C. A. J. Ribeiro M. Wajner G. Leipnitz (&) Departamento de Bioquı´mica, Instituto de Cieˆncias Ba´sicas da Sau´de, Universidade Federal de Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, Porto Alegre, RS CEP 90035-003, Brazil e-mail: [email protected] M. Wajner Servic¸o de Gene´tica Me´dica do Hospital de Clı´nicas de Porto Alegre, Porto Alegre, RS, Brazil
prevented the inhibitory effects of GLY on creatine kinase and respiratory complexes in cerebral cortex and striatum. Our data indicate that crucial pathways for energy production and intracellular energy transfer are severely compromised by GLY. It is proposed that bioenergetic impairment induced by GLY in vivo may contribute to the neurological dysfunction found in patients affected by NKH. Keywords Nonketotic hyperglycinemia Glycine Energy metabolism Cerebral cortex Striatum
Introduction Nonketotic hyperglycinemia (NKH), also termed glycine encephalopathy, is an autosomal recessive inborn error of glycine (GLY) catabolism with a prevalence estimated in 1:60,000 newborns (Applegarth et al. 2000). This disorder is caused by a de
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