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J. Biol. Chem., Vol. 278, Issue 49, 48997-49005, December 5, 2003

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Mmm1p Spans Both the Outer and Inner Mitochondrial Membranes and Contains Distinct Domains for Targeting and Foci Formation^*

Noriko Kondo-Okamoto, Janet M. Shaw, and Koji Okamoto

From the Department of Biology, University of Utah, Salt Lake City, Utah 84112

In the yeast Saccharomyces cerevisiae, the integral membrane protein Mmm1p is required for maintenance of mitochondrial morphology and retention of mitochondrial DNA (mtDNA). Mmm1p localizes to discrete foci on mitochondria that are adjacent to mtDNA nucleoids in the matrix, raising the possibility that this protein plays a direct role in organizing, replicating, or segregating mtDNA. Although Mmm1p has been shown to cross the outer membrane with its C terminus facing the cytoplasm, the location of the N terminus has not been resolved. Here we show that Mmm1p spans both the outer and inner mitochondrial membranes, exposing its N terminus to the matrix. Surprisingly, deletion of the N-terminal extension decreased steady-state levels of the Mmm1 protein but did not affect mitochondrial morphology or mtDNA maintenance. Moreover, expression of Neurospora crassa MMM1, which naturally lacks a long N-terminal extension, substituted for loss of Mmm1p in budding yeast. These results indicate that the matrix-exposed portion of Mmm1p is not essential for mtDNA nucleoid maintenance. Additional studies revealed that the transmembrane segment and C-terminal domain of Mmm1p are required for foci formation and mitochondrial targeting, respectively. Our data suggest that the double membrane-spanning topology of Mmm1p at the membrane contact site is critical for formation of tubular mitochondria.

Received for publication, August 1, 2003 , and in revised form, September 10, 2003.

^* This work was supported in part by National Institutes of Health Grant GM-53466 (to J. M. S.) and by a grant from the United Mitochondrial Disease Foundation (to K. O.). The University of Utah DNA and Peptide Facility was supported in part by NCI, National Institutes of Health Grant CA42014. 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.

To whom correspondence may be addressed: Dept. of Biology, University of Utah, 257 S. 1400 E., Salt Lake City, UT 84112. Tel.: 801-585-6205; Fax: 801-581-2174; E-mail: shaw{at}bioscience.utah.edu. To whom correspondence may be addressed: Dept. of Biology, University of Utah, 257 S. 1400 E., Salt Lake City, UT 84112. Tel.: 801-587-9209; Fax: 801-581-2174; E-mail: kokamoto{at}biology.utah.edu.

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