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.
Highlights
There is a growing interest in molecular mechanisms regulating oxidative phosphorylation capacity because of the increasing number of diseases associated with mitochondrial dysfunction [1] and as aging is associated with mitochondrial functional decline [2,3]
We make one step forward by unraveling a new role for the mitochondrial transcription termination factor 3 (MTERF3), which was initially characterized as a factor able to decrease mitochondrial transcription
We show in two distinct model organisms, the fruit fly and the mouse, that MTERF3 is involved in mitochondrial transcription and favors the assembly of the mitochondrial ribosome and thereby reinforces the coordination between transcription and translation events, two key steps in mitochondrial genome expression
Summary
There is a growing interest in molecular mechanisms regulating oxidative phosphorylation capacity because of the increasing number of diseases associated with mitochondrial dysfunction [1] and as aging is associated with mitochondrial functional decline [2,3]. Regulation of mitochondrial gene expression has an important role in fine-tuning oxidative phosphorylation capacity because critical subunits of the respiratory chain and the ATP synthase are encoded by mitochondrial DNA (mtDNA) [4,5]. There are a large number of mtDNA molecules in any given cell and changes in copy number are a slow process that is unlikely to have a main regulatory importance. In support of this notion, experimental manipulation of TFAM expression has been used to create mouse models with moderate decrease or increase of mtDNA copy number, with no or only minor effects on oxidative phosphorylation capacity [10,13]
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