GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I.
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.
Huang
Guochang
G
Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Proteos Building, Room 6-19B, 61 Biopolis Dr., Singapore 138673, Republic of Singapore.
Lu
Hao
H
Hao
Aijun
A
Ng
Dominic C H
DC
Ponniah
Sathivel
S
Guo
Ke
K
Lufei
Chengchen
C
Zeng
Qi
Q
Cao
Xinmin
X
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
D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse; D042967:Electron Transport Complex I