MTERF3 Regulates Mitochondrial Ribosome Biogenesis in Invertebrates and Mammals

Abstract

Regulation of mitochondrial DNA (mtDNA) expression is critical for the control of oxidative phosphorylation in response to physiological demand, and this regulation is often impaired in disease and aging. We have previously shown that mitochondrial transcription termination factor 3 (MTERF3) is a key regulator that represses mtDNA transcription in the mouse, but its molecular mode of action has remained elusive. Based on the hypothesis that key regulatory mechanisms for mtDNA expression are conserved in metazoans, we analyzed Mterf3 knockout and knockdown flies. We demonstrate here that decreased expression of MTERF3 not only leads to activation of mtDNA transcription, but also impairs assembly of the large mitochondrial ribosomal subunit. This novel function of MTERF3 in mitochondrial ribosomal biogenesis is conserved in the mouse, thus we identify a novel and unexpected role for MTERF3 in coordinating the crosstalk between transcription and translation for the regulation of mammalian mtDNA gene expression.

Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans

“…Several studies indicate a close relationship between the rDNA arrays, ribosomal biogenesis and the mitochondria [10][11][12][13] . For instance, recent evidence points to the import of 5S rRNAs into the mitochondria through a highly regulated process 35,36 .…”

“…NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5850 ARTICLE This protein regulates mitochondrial transcription and mitochondrial ribosome biogenesis 12 . These results suggest tight regulatory relationship between rDNA dosage, GE of ribosomal proteins and mtDNA abundance, which emerge in the context of naturally occurring variability among individuals (Fig.…”

“…1), are present at variable levels in cells and interact with nuclear ribosomes through coordinated processes [8][9][10] . Indeed, functional relationships between the rRNA transcription and the mitochondria are evident [10][11][12][13] . Finally, analyses in Drosophila indicated that the expression of genes that localize to the mitochondria is responsive to engineered deletions that decreased rDNA CN 8 .…”

Mitochondrial Ribosomal RNA (rRNA) Methyltransferase Family Members Are Positioned to Modify Nascent rRNA in Foci near the Mitochondrial DNA Nucleoid

“…First, Surovtseva and Shadel (53) reported that mtRNA polymerase has a transcription-independent role in ribosome assembly, dependent to some degree on the interaction of mtRNA polymerase with the methyltransferase TFB1M. Second, Larsson's group (54) has shown that MTERF3 is both a negative regulator of mitochondrial transcription and a factor involved in mitochondrial ribosome assembly (55). MTERF3 and mtRNA polymerase were both identified as interacting with RNMTL1, possibly mediated by RNA structures (Table 1).…”

A Member of the Arabidopsis Mitochondrial Transcription Termination Factor Family Is Required for Maturation of Chloroplast Transfer RNAIle(GAU)

“…Knockout Mterf3 mice are embryo lethal (Park et al, 2007). In the conditional Mterf3 heart knockout, levels of the 39S mitochondrial ribosomal subunit are reduced and ribosomal assembly is perturbed (Wredenberg et al, 2013); thereby, a novel role for mouse mTERF3 in the biogenesis of metazoan mitochondrial ribosomes was identified. Like Mterf3 knockout mice (Park et al, 2007), Mterf4 knockout mice are embryo lethal (Cámara et al, 2011).…”