TY - JOUR

T1 - The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation

AU - Zhao, Jian

AU - Liu, Tong

AU - Jin, Shao Bo

AU - Tomilin, Nikolay

AU - Castro, Juan

AU - Shupliakov, Oleg

AU - Lendahl, Urban

AU - Nistér, Monica

PY - 2009/7/1

Y1 - 2009/7/1

N2 - 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 γ-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.

AB - 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 γ-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.

KW - Brain tumor

KW - Cell proliferation

KW - GxxxG motif

KW - Mitochondrial fission

KW - Mitochondrial membrane protein

UR - http://www.scopus.com/inward/record.url?scp=69449090286&partnerID=8YFLogxK

U2 - 10.1242/jcs.038513

DO - 10.1242/jcs.038513

M3 - Article

C2 - 19535734

AN - SCOPUS:69449090286

VL - 122

SP - 2252

EP - 2262

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 13

ER -