An Essential Role for COPI in mRNA Localization to Mitochondria and Mitochondrial Function

Abstract

Nuclear-encoded mRNAs encoding mitochondrial proteins (mMPs) can localize directly to the mitochondrial surface, yet how mMPs target mitochondria and whether RNA targeting contributes to protein import into mitochondria and cellular metabolism are unknown. Here, we show that the COPI vesicle coat complex is necessary for mMP localization to mitochondria and mitochondrial function. COPI inactivation leads to reduced mMP binding to COPI itself, resulting in the dissociation of mMPs from mitochondria, a reduction in mitochondrial membrane potential, a decrease in protein import in vivo and in vitro, and severe deficiencies in mitochondrial respiration. Using a model mMP (OXA1), we observed that COPI inactivation (or mutation of the potential COPI-interaction site) led to altered mRNA localization and impaired cellular respiration. Overall, COPI-mediated mMP targeting is critical for mitochondrial protein import and function, and transcript delivery to the mitochondria or endoplasmic reticulum is regulated by cis-acting RNA sequences and trans-acting proteins.

Regulation by 3′-Untranslated Regions

“…For instance, the RBPs HuD and RAVER1 were shown to interact with actin-binding proteins and with microtubule-associated proteins, respectively (35,52). mRNAs also bind to several components of vesicle coats, including COPI and COPII vesicle coat complexes (127,146), and were found to localize to the surface of different organelles, such as mitochondria, endosomes, or the endoplasmic reticulum (25,38,60,105). These examples show an intimate association between mRNAs, membranes, and the cytoskeleton.…”

Cytosolic ribosomes on the surface of mitochondria

“…Additionally, various independent approaches have shown an enrichment of mRNAs encoding mitochondrial proteins, either on the mitochondrial surface or in close proximity, both in yeast [22-27] and human cells [28, 29]. Their association was dependent on COP1-mediated targeting [30] and involved the outer membrane-associated protein Puf3, which binds 3’ non-coding sequences of mRNAs [31, 32]. Mitochondrial surface-localized mRNA molecules were also found to be active as templates for protein synthesis [27].…”

Formation of COPI-coated vesicles at a glance

“…COPI operates in retrieval from the Golgi to the endoplasmic reticulum (ER) and in intra-Golgi transport (Beck et al, 2009;Duden, 2003;Lee et al, 2004a;Spang, 2009), and maintains ER-and Golgi-resident chaperones and enzymes where they belong. Several reports have also highlighted a role for COPI in endosomal transport and function (Aniento et al, 1996;Daro et al, 1997;Gabriely et al, 2006;Gu et al, 1997;Guo et al, 1994;Razi et al, 2009;Whitney et al, 1995), regulating lipid droplet homeostasis (Beller et al, 2008;Soni et al, 2009;Thiam et al, 2013;Wilfling et al, 2013), mRNA transport (Bi et al, 2007;Todd et al, 2013;Trautwein et al, 2004;Zabezhinsky et al, 2016), and the breakdown of the nuclear envelope (Liu et al, 2003;Prunuske et al, 2006). Discussion of these roles is beyond the scope of this review (see textbox for some open questions).…”