Clueless is a conserved ribonucleoprotein that binds the ribosome at the mitochondrial outer membrane

Abstract

Mitochondrial function is tied to the nucleus, in that hundreds of proteins encoded by nuclear genes must be imported into mitochondria. While post-translational import is fairly well understood, emerging evidence supports that mitochondrial site-specific import, or co-translational import, also occurs. However, the mechanism and the extent to which it is used are not fully understood. We have previously shown Clueless (Clu), a conserved multi-domain protein, associates with mitochondrial outer membrane proteins, including Translocase of outer membrane 20, and genetically and physically interacts with the PINK1–Parkin pathway. The human ortholog of Clu, Cluh, was shown to bind nuclear-encoded mitochondrially destined mRNAs. Here we identify the conserved tetratricopeptide domain of Clu as predominantly responsible for binding mRNA. In addition, we show Clu interacts with the ribosome at the mitochondrial outer membrane. Taken together, these data support a model whereby Clu binds to and mitochondrially targets mRNAs to facilitate mRNA localization to the outer mitochondrial membrane, potentially for site-specific or co-translational import. This role may link the presence of efficient mitochondrial protein import to mitochondrial quality control through the PINK1–Parkin pathway.

The key protein of endosomal mRNP transport Rrm4 binds translational landmark sites of cargo mRNAs

“…These results agree with previous findings that the 3′ UTR of ATP2 mRNA from S. cerevisiae is important for efficient mitochondrial uptake of mature Atp2p . A close link between RNA biology and mitochondrial protein import is thus an emerging theme in mitochondrial biology .…”

CLUH couples mitochondrial distribution to the energetic and metabolic status

“…In our cellular model, the mtDNA abundance remained unaffected, but the mitochondrial protein synthesis was significantly reduced in the absence of CLUH, suggesting a major alteration of the mitochondrial translation process. Beside the importance of CLUH on mRNA translation of nuclear-encoded mitochondrial proteins (Gao et al, 2014;Sen and Cox, 2016), the evidence that PINK1 and Parkin also control the mRNA translation of the respiratory chain subunits at the outer mitochondrial membrane (Gehrke et al, 2015) suggests that a concerted regulation of all the respiratory components encoded by the nuclear and mitochondrial genomes can be achieved by a crosstalk between CLUH and the PINK-Parkin pathway. Thus, the decrease in the mitochondrial translation machinery in CLUH-KO cells without mtDNA defects raises questions about both the stability of mitochondrial mRNA and the regulation of specific downstream effects on the mRNAs that are targeted by CLUH (Schatton et al, 2017).…”

“…More recently, Gao et al have reported that human CLUH interacts with a subset of mRNAs encoding mitochondrial proteins, suggesting that CLUH is also involved in mitochondrial biogenesis (Gao et al, 2014). Support for this role has also been provided by studies in Drosophila, which demonstrated that CLU is a ribonucleoprotein binding ribosomal components at the mitochondrial outer membrane (Sen and Cox, 2016). Clearly, further studies are needed to understand whether alteration in mitochondrial distribution in CLUH-depleted cells is a primary effect or secondary to mitochondrial biogenesis defects.…”

Clueless forms dynamic, insulin-responsive bliss particles sensitive to stress

“…Loss of clu in Drosophila is adult lethal. In uncrowded conditions, larvae are able to pupate after a short developmental delay, but the adults die after 4-7 days and look sickly immediately following eclosion (Sen and Cox, 2016;Sen et al, 2013). ATP levels are normal in larvae however levels are greatly decreased in adults who accumulate mitochondrial oxidative damage (Sen et al, 2013).…”

“…Clu's role in regulating mitochondrial function and metabolism is due to its role in mRNA regulation. Clu, Cluh and yeast Clu1p are ribonucleoproteins (RNPs) (Gao et al, 2014;Schatton et al, 2017;Sen and Cox, 2016). Cluh binds and regulates mRNAs encoding proteins that will be imported into mitochondria (Gao et al, 2014;Schatton et al, 2017).…”