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Published 31 July 2006. doi:10.1083/jcb.200605043
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 3, 379-390
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Article

Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins



Steven M. Claypool1, J. Michael McCaffery3, and Carla M. Koehler1,2

1 Department of Chemistry and Biochemistry and 2 the Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095
3 Integrated Imaging Center, Department of Biology, Johns Hopkins University, Baltimore, MD 21218

Correspondence to Carla M. Koehler: Koehler{at}chem.ucla.edu

None of the 28 identified point mutations in tafazzin (Taz1p), which is the mutant gene product associated with Barth syndrome (BTHS), has a biochemical explanation. In this study, endogenous Taz1p was localized to mitochondria in association with both the inner and outer mitochondrial membranes facing the intermembrane space (IMS). Unexpectedly, Taz1p does not contain transmembrane (TM) segments. Instead, Taz1p membrane association involves a segment that integrates into, but not through, the membrane bilayer. Residues 215–232, which were predicted to be a TM domain, were identified as the interfacial membrane anchor by modeling four distinct BTHS mutations that occur at conserved residues within this segment. Each Taz1p mutant exhibits altered membrane association and is nonfunctional. However, the basis for Taz1p dysfunction falls into the following two categories: (1) mistargeting to the mitochondrial matrix or (2) correct localization associated with aberrant complex assembly. Thus, BTHS can be caused by mutations that alter Taz1p sorting and assembly within the mitochondrion, indicating that the lipid target of Taz1p is resident to IMS-facing leaflets.

Abbreviations used in this paper: AAC, ADP/ATP carrier; ANOVA, analysis of variance; BTHS, Barth syndrome; CL, cardiolipin; IM, inner membrane; IMS, intermembrane space; KDH, {alpha}–ketoglutarate dehydrogenase; MLCL, monolysocardiolipin; OM, outer membrane; PC, phosphatidylcholine; PE, phosphatidylethanolamine; TM, transmembrane; wt, wild type.


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