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J. Biol. Chem., Vol. 279, Issue 43, 44394-44399, October 22, 2004
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Mutant




¶
From the
Department of Biological Sciences, Wayne State University, Detroit, Michigan, 48202 and the
Departments of Clinical Chemistry and Pediatrics, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Barth syndrome is a genetic disorder that is caused by different mutations in the TAZ gene G4.5. The yeast gene TAZ1 is highly homologous to human TAZ, and the taz1
mutant has phospholipid defects similar to those observed in Barth syndrome cells, including aberrant cardiolipin species and decreased cardiolipin levels. Subcellular fractionation studies revealed that Taz1p is localized exclusively in mitochondria, which supports the theory that tafazzins are involved in cardiolipin remodeling. Because cardiolipin plays an important role in respiratory function, we measured the energy transformation and osmotic properties of isolated mitochondria from the taz1
mutant. Energy coupling in taz1
mitochondria was dependent on the rate of oxidative phosphorylation, as coupling was diminished when NADH was used as a respiratory substrate but was unaffected when ethanol was the substrate. Membrane stability was compromised in taz1
mitochondria exposed to increased temperature and hypotonic conditions. Mitochondria from taz1
also displayed decreased swelling in response to ATP, which induces the yeast mitochondrial unspecific channel, and to alamethicin, a membrane-disrupting agent. Coupling was measured in taz1
cells containing different splice variants of the human TAZ gene. Only the variant that restores wild type cardiolipin synthesis (lacking exon 5) restored coupling in hypotonic conditions and at elevated temperature. These findings may shed light on the mitochondrial deficiencies observed in Barth syndrome.
Received for publication, May 17, 2004 , and in revised form, July 21, 2004.
* This work was supported by National Institutes of Health Grant HL62263 (to M. L. G.); by Princess Beatrix Fund, the Hague, The Netherlands, Grant MAR010129 (to R. J. A. W.); and Barth Syndrome Foundation grants (to M. L. G. and F. M. V). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This paper is dedicated to the memory of Evan Bowen.
¶ To whom correspondence should be addressed. Tel.: 313-577-5201; Fax: 313-577-6891; E-mail: MLGREEN{at}sun.science.wayne.edu.
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