Publication Date

2012-01-19

Availability

Open access

Embargo Period

2012-01-19

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2012-12-09

First Committee Member

Zafar Nawaz

Second Committee Member

Antonio Barrientos

Third Committee Member

Murray P. Deutscher

Fourth Committee Member

Carlos Moraes

Fifth Committee Member

Xochitl Perez-Martinez

Abstract

In eukaryotic cells, energy is produced by the coordinated action of the mitochondrial respiratory chain (MRC) and the oxidative phosphorylation system (OXPHOS). Cytochrome c oxidase (COX) is the fourth enzyme of the MRC. COX catalytic activity is mediated by prosthetic groups located in subunits 1 (Cox1) and 2. More than twenty nuclear encoded factors are required for the assembly of the functional enzyme. Cox1 is the center of a regulatory mechanism in which its protein levels depend on the availability of its assembly partners. A key element in the regulatory pathway is the nuclear encoded factor Mss51, a protein essential for COX1 mRNA translation and Cox1 stability. In this thesis work, we show that Mss51 performs these two functions by dynamically interacting with several protein partners, including COX assembly chaperones and the Hsp70 general chaperone Ssc1. We have also characterized functional domains in Mss51. Specifically, we are reporting the presence of two conserved CPX (Val,Leu) heme-binding motifs, essential for in vivo Mss51 functions. Our data supports a system in which the efficiency of Mss51 as a translational activator is regulated by heme levels perhaps in a redox-sensitive manner. This study contributes to the current knowledge and understanding of the COX assembly process by disclosing new mechanisms involved in its intricate regulation.

Keywords

Mss51, heme, mitochondrial translation, COX assembly

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