GRIM-19, a Cell Death Regulatory Protein, Is Essential for Assembly and Function of Mitochondrial Complex I
- 1 October 2004
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 24 (19), 8447-8456
- https://doi.org/10.1128/mcb.24.19.8447-8456.2004
Abstract
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.Keywords
This publication has 39 references indexed in Scilit:
- Disruption of the COP9 Signalosome Csn2 Subunit in Mice Causes Deficient Cell Proliferation, Accumulation of p53 and Cyclin E, and Early Embryonic DeathMolecular and Cellular Biology, 2003
- Mitochondria: Releasing Power for Life and Unleashing the Machineries of DeathCell, 2003
- Structures and Proton-Pumping Strategies of Mitochondrial Respiratory EnzymesAnnual Review of Biophysics and Biophysical Chemistry, 2001
- Respiratory chain complex I deficiencyAmerican Journal of Medical Genetics, 2001
- Mitochondrial diseases: Beyond the magic circleAmerican Journal of Medical Genetics, 2001
- Cytochrome c Deficiency Causes Embryonic Lethality and Attenuates Stress-Induced ApoptosisCell, 2000
- Supercomplexes in the respiratory chains of yeast and mammalian mitochondriaThe EMBO Journal, 2000
- HOW CELLS RESPOND TO INTERFERONSAnnual Review of Biochemistry, 1998
- Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathwayCell, 1994
- The NADH:ubiquinone oxidoreductase (complex I) of respiratory chainsQuarterly Reviews of Biophysics, 1992