Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders

Giuseppe Battaglia, Maria Grazia Farrace, Pier Giorgio Mastroberardino, Irene Viti, Gian Maria Fimia, Jozef Van Beeumen, Bart Devreese, Gennaro Melino, Gemma Molinaro, Carla Letizia Busceti, Francesca Biagioni, Ferdinando Nicoletti, Mauro Piacentini

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Transglutaminase 2 (TG2) represents the most ubiquitous isoform belonging to the TG family, and has been implicated in the pathophysiology of basal ganglia disorders, such as Parkinson's disease and Huntington's disease. We show that ablation of TG2 in knockout mice causes a reduced activity of mitochondrial complex I associated with an increased activity of complex II in the whole forebrain and striatum. Interestingly, TG2-/- mice were protected against nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, which is converted in vivo into the mitochondrial complex I inhibitor, 1-methyl-4-phenyl-pyridinium ion. In contrast, TG2-/- mice were more vulnerable to nigrostriatal damage induced by methamphetamine or by the complex II inhibitor, 3-nitropropionic acid. Proteomic analysis showed that proteins involved in the mitochondrial respiratory chain, such as prohibitin and the β-chain of ATP synthase, are substrates for TG2. These data suggest that TG2 is involved in the regulation of the respiratory chain both in physiology and pathology, contributing to set the threshold for neuronal damage in extrapyramidal disorders.

Original languageEnglish (US)
Pages (from-to)36-49
Number of pages14
JournalJournal of Neurochemistry
Volume100
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • 3-nitropropionic acid toxicity
  • Basal ganglia
  • Methamphetamine toxicity
  • Mitochondria
  • Transglutaminase 2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Battaglia, G., Farrace, M. G., Mastroberardino, P. G., Viti, I., Fimia, G. M., Van Beeumen, J., Devreese, B., Melino, G., Molinaro, G., Busceti, C. L., Biagioni, F., Nicoletti, F., & Piacentini, M. (2007). Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders. Journal of Neurochemistry, 100(1), 36-49. https://doi.org/10.1111/j.1471-4159.2006.04140.x