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First published online June 17, 2009
doi: 10.1242/10.1242/jcs.038513

Journal of Cell Science 122, 2252-2262 (2009)
Published by The Company of Biologists 2009
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Research Article

The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation

Jian Zhao1,*, Tong Liu1, Shao-Bo Jin2, Nikolay Tomilin3, Juan Castro1, Oleg Shupliakov3, Urban Lendahl2 and Monica Nistér1,*

1 Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden
2 Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
3 Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden

* Authors for correspondence (e-mails: Jian.Zhao{at}ki.se; Monica.Nister{at}ki.se)

Accepted 25 March 2009

Although several proteins involved in mediating mitochondrial division have been reported in mammals, the mechanism of the fission machinery remains to be elucidated. Here, we identified a human nuclear gene (named MTGM) that encodes a novel, small, integral mitochondrial inner-membrane protein and shows high expression in both human brain tumor cell lines and tumor tissues. The gene is evolutionarily highly conserved, and its orthologs are 100% identical at the amino acid level in all analyzed mammalian species. The gene product is characterized by an unusual tetrad of the GxxxG motif in the transmembrane segment. Overexpression of MTGM (mitochondrial targeting GxxxG motif) protein results in mitochondrial fragmentation and release of mitochondrial Smac/Diablo to the cytosol with no effect on apoptosis. MTGM-induced mitochondrial fission can be blocked by a dominant negative Drp1 mutant (Drp1-K38A). Overexpression of MTGM also results in inhibition of cell proliferation, stalling of cells in S phase and nuclear accumulation of {gamma}-H2AX. Knockdown of MTGM by RNA interference induces mitochondrial elongation, an increase of cell proliferation and inhibition of cell death induced by apoptotic stimuli. In conclusion, we suggest that MTGM is an integral mitochondrial inner-membrane protein that coordinately regulates mitochondrial morphology and cell proliferation.

Key words: Mitochondrial fission, Mitochondrial membrane protein, Cell proliferation, GxxxG motif, Brain tumor


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