MTERF3 is a negative regulator of mammalian mtDNA transcription.
Regulation of mammalian mtDNA gene expression is critical for altering oxidative phosphorylation capacity in response to physiological demands and disease processes. The basal machinery for initiation of mtDNA transcription has been molecularly defined, but the mechanisms regulating its activity are poorly understood. In this study, we show that MTERF3 is a negative regulator of mtDNA transcription initiation. The MTERF3 gene is essential because homozygous knockout mouse embryos die in midgestation. Tissue-specific inactivation of MTERF3 in the heart causes aberrant mtDNA transcription and severe respiratory chain deficiency. MTERF3 binds the mtDNA promoter region and depletion of MTERF3 increases transcription initiation on both mtDNA strands. This increased transcription initiation leads to decreased expression of critical promoter-distal tRNA genes, which is possibly explained by transcriptional collision on the circular mtDNA molecule. To our knowledge, MTERF3 is the first example of a mitochondrial protein that acts as a specific repressor of mammalian mtDNA transcription initiation in vivo.
Park
Chan Bae
CB
Department of Laboratory Medicine, Karolinska Institutet, S-141 86 Stockholm, Sweden.
Asin-Cayuela
Jorge
J
Cámara
Yolanda
Y
Shi
Yonghong
Y
Pellegrini
Mina
M
Gaspari
Martina
M
Wibom
Rolf
R
Hultenby
Kjell
K
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Falkenberg
Maria
M
Gustafsson
Claes M
CM
Larsson
Nils-Göran
NG
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D004579:Electron Transport; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D018390:Gene Targeting; D020043:Genes, Essential; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004272:DNA, Mitochondrial; C522573:MTERF3 protein, mouse; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D014157:Transcription Factors