Mss51 and Ssc1 Facilitate Translational Regulation of Cytochrome c Oxidase Biogenesis

Abstract

The intricate biogenesis of multimeric organellar enzymes of dual genetic origin entails several levels of regulation. In Saccharomyces cerevisiae, mitochondrial cytochrome c oxidase (COX) assembly is regulated translationally. Synthesis of subunit 1 (Cox1) is contingent on the availability of its assembly partners, thereby acting as a negative feedback loop that coordinates COX1 mRNA translation with Cox1 utilization during COX assembly. The COX1 mRNA-specific translational activator Mss51 plays a fundamental role in this process. Here, we report that Mss51 successively interacts with the COX1 mRNA translational apparatus, newly synthesized Cox1, and other COX assembly factors during Cox1 maturation/assembly. Notably, the mitochondrial Hsp70 chaperone Ssc1 is shown to be an Mss51 partner throughout its metabolic cycle. We conclude that Ssc1, by interacting with Mss51 and Mss51-containing complexes, plays a critical role in Cox1 biogenesis, COX assembly, and the translational regulation of these processes.

hCOA3 Stabilizes Cytochrome c Oxidase 1 (COX1) and Promotes Cytochrome c Oxidase Assembly in Human Mitochondria

“…Mss51, the central protein of a negative feedback translational regulatory system in yeast, has a dual function acting as a translational activator of COX1 mRNA and as a COX1 chaperone during the first steps of COX biogenesis (39). During and after synthesis, COX1 is bound to Mss51 in a complex stabilized by two small COX-specific chaperones, Cox14 (40) and Coa3 (37,38) and the mitochondrial Hsp70 chaperone (41). When COX1 pro-FIGURE 8. hCOA3 interacts with COX structural subunits and complex I.…”

“…ceeds in the assembly process, Mss51 is released from these complexes and is available to activate new rounds of Cox1 synthesis (41)(42)(43).…”

Mne1 Is a Novel Component of the Mitochondrial Splicing Apparatus Responsible for Processing of a COX1 Group I Intron in Yeast

“…Newly synthesized Cox1 readily associates with the Mss51 translational activator as the initial Cox1 assembly intermediate (45,46). Formation of the ϳ440 kDa Mss51 complex containing Cox1, Cox14, and Ssc1 correlates with Cox1 translation and early assembly (46).…”

“…Formation of the ϳ440 kDa Mss51 complex containing Cox1, Cox14, and Ssc1 correlates with Cox1 translation and early assembly (46). The presence of the high mass Mss51 complex was assessed in mne1⌬ cells containing a chromosomally Myc-tagged Mss51.…”

Mechanisms of mitochondrial translational regulation

“…Mss51 dynamically interacts with newly synthesized Cox1, promoting its stability and its incorporation into COX subcomplexes, and with several components of the COX biogenetic process (26,27). During Cox1 synthesis on the mitochondrial ribosomes, Mss51 interacts with newly synthesized Cox1, in a complex that also contains the mitochondrial Hsp70 chaperone Ssc1, its cochaperone Mdj1 and the two COX assembly factors Cox14 and Coa3 (26,28). After Cox1 synthesis and Oxa1-dependent membrane insertion, an Ssc1-Mss51-Cox1-Cox14-Coa3 preassembly complex is formed (26,28,29).…”