Mitochondrial aconitase is a transglutaminase 2 substrate: transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain.
Transglutaminase activity was found to be present in highly purified non-synaptosomal rat brain mitochondria. A 78-kDa protein in these organelles was shown to be a transglutaminase 2 substrate, and incubation of a non-synaptosomal mitochondrial lysate with transglutaminase 2 yielded high-Mr proteins. The 78-kDa protein was identified as mitochondrial aconitase by MALDI-TOF analysis. Aconitase activity was decreased in a dose-dependent manner when non-synaptosomal rat brain mitochondria were incubated with transglutaminase 2. Transglutaminase activity is increased about 2-fold in the mitochondrial fraction of HD caudate. Moreover, Western blotting of the mitochondrial fraction revealed that most of the mitochondrial aconitase in HD caudate is present as high-Mr aggregates. Aconitase activity was previously shown to be decreased in Huntington disease (HD) caudate (a region severely damaged by the disease). The present findings suggest that an increase of transglutaminase activity in HD caudate may contribute to mitochondrial dysfunction by incorporating aconitase into inactive polymers.
Kim
Soo-Youl
SY
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.
Marekov
Lyuben
L
Bubber
Parvesh
P
Browne
Susan E
SE
Stavrovskaya
Irina
I
Lee
Jongmin
J
Steinert
Peter M
PM
Blass
John P
JP
Beal
M Flint
MF
Gibson
Gary E
GE
Cooper
Arthur J L
AJ
D000154:Aconitate Hydratase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000201:enzymology* / Q000473:pathology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D008970:Molecular Weight; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013347:Subcellular Fractions / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*
D010455:Peptides; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D000154:Aconitate Hydratase