Cytochrome c oxidase (COX) deficiency is the most frequent cause of mitochondrial encephalomyopathies in humans and has also been associated to neurodegeneration and aging. A better understanding of COX biogenesis is essential for elucidating the molecular basis underlying these groups of diseases. The main objective of the proposed research is to investigate the players and mechanisms involved in COX biogenesis using the yeast Saccharomyces cerevisiae and cultured human cells as research models. Our long-term goal is to attain a complete understanding of the pathways leading to COX assembly and their components as a prerequisite to the development of therapies for the management of disorders associated with COX deficiencies. In the previous term of our grant we made significant progress in the understanding of how COX biogenesis is regulated. Eukaryotic COX is a multimeric enzyme formed by polypeptides of dual genetic origin (nuclear and mitochondrial) which assembly involves a large number of nuclear-encoded auxiliary factors. COX display a concerted accumulation of its constitutive subunits. Unassembled subunits bear a high risk to produce reactive oxygen species and their accumulation is limited by posttranslational degradation. We have revealed another contribution to the stoichiometric accumulation of subunits during COX biogenesis. Our data support the existence of a regulatory mechanism by which the synthesis of mtDNA-encoded COX subunit 1 (Cox1) is regulated by the availability of its assembly partners in the yeast Saccharomyces cerevisiae. Thus, the central hypothesis of this proposal is the existence of a COX assembly dependent regulation of Cox1 synthesis, which unique properties, in turn, offer a means to catalyze multiple- subunit assembly. In S. cerevisiae, the regulatory system involves specific COX1 mRNA translational activators, specific Cox1 chaperones and assembly factors as well as general chaperones acting together in a sophisticated interplay that we are just beginning to characterize. The central element of the regulatory system is the bi-functional COX1 mRNA translational activator and Cox1 chaperone Mss51 which is conserved from yeast to humans.
Three specific aims are proposed to characterize recently identified new Mss51-interacting players (i.e. Ssc1 and Cox25) and levels of complexity (i.e. Mss51 is a heme binding protein) concerning the translational regulatory system in S. cerevisiae and its conservation from yeast to humans.
Aim # 1 - Disclose the mechanism and role of heme binding by Mss51 Aim #2 - Investigate the mechanism/s by which the interactions of Mss51 with mitochondrial chaperones regulate Cox1 synthesis Aim # 3 - Determine the functional equivalence of yeast and human Mss51
Cytochrome c oxidase (COX) deficiency is the most frequent cause of mitochondrial encephalomyopathies in humans and has also been associated to neurodegeneration and aging. We will use the yeast Saccharomyces cerevisiae and human cultured cells to study the function of Mss51, a protein that plays dual functions in the synthesis of COX subunit 1 and in the assembly of this subunit into the COX holoenzyme. To gain knowledge on the function of this protein and the pathways in which it operates to regulate COX biogenesis is of great importance from a biological point of view and is expected to have an impact on our understanding of the pathogenic mechanisms underlying the above-mentioned kind of disorders.
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