The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation.
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.
Zhao
Jian
J
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. Jian.Zhoa@ki.se
Liu
Tong
T
Jin
Shao-Bo
SB
Tomilin
Nikolay
N
Castro
Juan
J
Shupliakov
Oleg
O
Lendahl
Urban
U
Nistér
Monica
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; C543706:MTGM protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins