TY - JOUR
T1 - Barth syndrome mutations that cause tafazzin complex lability
AU - Claypool, Steven M.
AU - Whited, Kevin
AU - Srijumnong, Santi
AU - Han, Xianlin
AU - Koehler, Carla M.
N1 - Funding Information:
This study is supported by grant 2012/33560 from the Ministerio de Economía y Competitividad, Spain, to JP and by a grant from the Leona M and Harry B Helmsley Charitable Trust to AS.
PY - 2011/2/7
Y1 - 2011/2/7
N2 - Deficits in mitochondrial function result in many human diseases. The X-linked disease Barth syndrome (BTHS) is caused by mutations in the tafazzin gene TAZ1. Its product, Taz1p, participates in the metabolism of cardiolipin, the signature phospholipid of mitochondria. In this paper, a yeast BTHS mutant tafazzin panel is established, and 18 of the 21 tested BTHS missense mutations cannot functionally replace endogenous tafazzin. Four BTHS mutant tafazzins expressed at low levels are degraded by the intermembrane space AAA (i-AAA) protease, suggesting misfolding of the mutant polypeptides. Paradoxically, each of these mutant tafazzins assembles in normal protein complexes. Furthermore, in the absence of the i-AAA protease, increased expression and assembly of two of the BTHS mutants improve their function. However, the BTHS mutant complexes are extremely unstable and accumulate as insoluble aggregates when disassembled in the absence of the i-AAA protease. Thus, the loss of function for these BTHS mutants results from the inherent instability of the mutant tafazzin complexes.
AB - Deficits in mitochondrial function result in many human diseases. The X-linked disease Barth syndrome (BTHS) is caused by mutations in the tafazzin gene TAZ1. Its product, Taz1p, participates in the metabolism of cardiolipin, the signature phospholipid of mitochondria. In this paper, a yeast BTHS mutant tafazzin panel is established, and 18 of the 21 tested BTHS missense mutations cannot functionally replace endogenous tafazzin. Four BTHS mutant tafazzins expressed at low levels are degraded by the intermembrane space AAA (i-AAA) protease, suggesting misfolding of the mutant polypeptides. Paradoxically, each of these mutant tafazzins assembles in normal protein complexes. Furthermore, in the absence of the i-AAA protease, increased expression and assembly of two of the BTHS mutants improve their function. However, the BTHS mutant complexes are extremely unstable and accumulate as insoluble aggregates when disassembled in the absence of the i-AAA protease. Thus, the loss of function for these BTHS mutants results from the inherent instability of the mutant tafazzin complexes.
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U2 - 10.1083/jcb.201008177
DO - 10.1083/jcb.201008177
M3 - Article
C2 - 21300850
AN - SCOPUS:79551700415
VL - 192
SP - 447
EP - 462
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 3
ER -