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Molecular and Cellular Biology, October 2004, p. 8447-8456, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8447-8456.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

GRIM-19, a Cell Death Regulatory Protein, Is Essential for Assembly and Function of Mitochondrial Complex I

Guochang Huang,1 Hao Lu,1 Aijun Hao,1 Dominic C. H. Ng,1 Sathivel Ponniah,2 Ke Guo,3 Chengchen Lufei,1 Qi Zeng,3 and Xinmin Cao1*

Signal Transduction Laboratory,1 In Vivo Model Systems Facility,2 Histology Unit, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore3

Received 3 June 2004/ Accepted 7 July 2004

Mitochondria play essential roles in cellular energy production via the oxidative phosphorylation system (OXPHOS) consisting of five multiprotein complexes and also in the initiation of apoptosis. NADH:ubiquinone oxidoreductase (complex I) is the largest complex that catalyzes the first step of electron transfer in the OXPHOS system. GRIM-19 was originally identified as a nuclear protein with apoptotic nature in interferon (IFN)- and all-trans-retinoic acid (RA)-induced tumor cells. To reveal its biological role, we generated mice deficient in GRIM-19 by gene targeting. Homologous deletion of GRIM-19 causes embryonic lethality at embryonic day 9.5. GRIM-19–/– blastocysts show retarded growth in vitro and, strikingly, display abnormal mitochondrial structure, morphology, and cellular distribution. We reexamined the cellular localization of GRIM-19 in various cell types and found its primary localization in the mitochondria. Furthermore, GRIM-19 is detected in the native form of mitochondrial complex I. Finally, we show that elimination of GRIM-19 destroys the assembly and electron transfer activity of complex I and also influences the other complexes in the mitochondrial respiratory chain. Our result demonstrates that GRIM-19, a gene product with a specific role in IFN-RA-induced cell death, is a functional component of mitochondrial complex I and is essential for early embryonic development.

* Corresponding author. Mailing address: Institute of Molecular and Cell Biology, Proteos Building, Room 6-19B, 61 Biopolis Dr., Singapore 138673, Republic of Singapore. Phone: 65 6586 9657. Fax: 65 6779 1117. E-mail: mcbcaoxm{at}imcb.a-star.edu.sg.

Molecular and Cellular Biology, October 2004, p. 8447-8456, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8447-8456.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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