title: GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I.
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.
authors.affiliation: Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Proteos Building, Room 6-19B, 61 Biopolis Dr., Singapore 138673, Republic of Singapore.
authors.forename: Guochang
authors.initials: G
authors.lastname: Huang
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.forename: Aijun
authors.initials: A
authors.lastname: Hao
authors.forename: Dominic C H
authors.initials: DC
authors.lastname: Ng
authors.forename: Sathivel
authors.initials: S
authors.lastname: Ponniah
authors.forename: Ke
authors.initials: K
authors.lastname: Guo
authors.forename: Chengchen
authors.initials: C
authors.lastname: Lufei
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.forename: Xinmin
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001755:Blastocyst / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D042967:Electron Transport Complex I / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; D042967:Electron Transport Complex I