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

• DOI: 10.1128/mcb.24.19.8447-8456.2004
• Publication Date: 2004-09-14T19:58:18Z
• Authors: Guochang Huang; Hao Lu; Aijun Hao; Dominic C. H. Ng; Sathivel Ponniah; Ke Guo; Chengchen Lufei; Qi Zeng; Xinmin Cao
• Keywords: Mice, Knockout; 0301 basic medicine; 570; Electron Transport Complex I; Microscopy, Confocal; Apoptosis; Cell Biology; Mitochondria; 1307 Cell Biology; Mice; 03 medical and health sciences; Blastocyst; 1312 Molecular Biology; Animals; NADH, NADPH Oxidoreductases; Molecular Biology; Cell Division; Sequence Deletion

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.