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Vol. 19, Issue 5, 1893-1902, May 2008

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GRIM-19 Is Essential for Maintenance of Mitochondrial Membrane Potential

Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, The Republic of Singapore

Submitted July 19, 2007; Revised January 28, 2008; Accepted February 7, 2008
Monitoring Editor: Donald Newmeyer

GRIM-19 was found to copurify with complex I of mitochondrial respiratory chain and subsequently was demonstrated to be involved in complex I assembly and activity. To further understand its function in complex I, we dissected its functional domains by generating a number of deletion, truncation, and point mutants. The mitochondrial localization sequences were located at the N-terminus. Strikingly, deletion of residues 70–80, 90–100, or the whole C-terminal region (70–144) led to a loss of mitochondrial transmembrane potential (m). However, similar deletions of another two complex I subunits, NDUFA9 and NDUFS3, did not show such effect. We also found that deletion of the last 10 residues affected GRIM-19's ability to be assembled to complex I. We constructed a dominant-negative mutant containing the N-terminal 60 and the last C-terminal 10 residues, which could be assembled into complex I, but failed to maintain normal m. Cells overexpressing this mutant did not spontaneously undergo cell death, but were sensitized to apoptosis induced by cell death agents. Our results demonstrate that GRIM-19 is required for electron transfer activity of complex I, and disruption of m by GRIM-19 mutants enhances the cells' sensitivity to apoptotic stimuli.

Address correspondence to: Xinmin Cao (mcbcaoxm{at}imcb.a-star.edu.sg)

Abbreviations used: aa, amino acids; m, mitochondrial transmembrane potential; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; IFN, interferon; GRIM, gene associated with retinoid-interferon–induced mortality; OXPHOS, oxidative phosphorylation; RA, all-trans-retinoic acid; RC, respiratory chain.