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Originally published In Press as doi:10.1074/jbc.M200003200 on June 17, 2002

J. Biol. Chem., Vol. 277, Issue 36, 33300-33310, September 6, 2002
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MLN64 Mediates Mobilization of Lysosomal Cholesterol to Steroidogenic Mitochondria*,

Mei ZhangDagger §, Pei Liu§, Nancy K. DwyerDagger , Lane K. Christenson, Toshio Fujimoto, Federico Martinez||, Marcy ComlyDagger , John A. Hanover**, E. Joan Blanchette-MackieDagger Dagger Dagger , and Jerome F. Strauss III§§

From the Dagger  Lipid Cell Biology Section and ** Cell Biochemistry Section, Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and  Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

This study demonstrates that the steroidogenic acute regulatory protein-related lipid transfer (START) domain-containing protein, MLN64, participates in intracellular cholesterol trafficking. Analysis of the intracellular itinerary of MLN64 and MLN64 mutants tagged with green fluorescent protein showed that the N-terminal transmembrane domains mediate endocytosis of MLN64 from the plasma membrane to late endocytic compartments. MLN64 constitutively traffics via dynamic NPC1-containing late endosomal tubules in normal cells; this dynamic movement was inhibited in cholesterol-loaded cells, and MLN64 is trapped at the periphery of cholesterol-laden lysosomes. The MLN64 START domain stimulated free cholesterol transfer from donor to acceptor mitochondrial membranes and enhanced steroidogenesis by placental mitochondria. Expression of a truncated form of MLN64 (Delta START-MLN64), which contains N-terminal transmembrane domains but lacks the START domain, caused free cholesterol accumulation in lysosomes and inhibited late endocytic dynamics. The Delta START-MLN64 dominant negative protein was located at the surface of the cholesterol-laden lysosomes. This dominant negative mutant suppressed steroidogenesis in COS cells expressing the mitochondrial cholesterol side chain cleavage system. We conclude that MLN64 participates in mobilization and utilization of lysosomal cholesterol by virtue of the START domain's role in cholesterol transport.

* This work was supported by National Institutes of Health Grant HD06274 (to J. F. S.) and a grant from the Ara Parseghian Medical Research Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains eight QuickTime movies.

§ Both authors contributed equally to this work.

|| A Visiting Scholar from the Department of Biochemistry, Universidad Nacional Autonoma de Mexico, supported by Fogarty International Center Grant D43-TW-00671.

Dagger Dagger To whom correspondence may be addressed: Lipid Cell Biology Section, Bldg. 8, Rm. 427, NIDDK, National Institutes of Health, 8 Center Dr., MSC 0851, Bethesda, MD 20892. Tel.: 301-496-2050; Fax: 301-402-0723; E-mail: joanbm@bdg8.niddk.nih.gov.

§§ To whom correspondence may be addressed: 1354 BRB II/III, University of Pennsylvania Medical Center, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-0147; Fax: 215-573-5408; E-mail: jfs3@mail.med.upenn.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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