Publication Date

2010-04-22

Availability

Open access

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2010-04-12

First Committee Member

Arun Malhotra - Committee Chair

Second Committee Member

Thomas K. Harris - Committee Member

Third Committee Member

Miguel Perez-Pinzon - Committee Member

Fourth Committee Member

Antoni Barrientos - Mentor

Fifth Committee Member

Carla Koehler - Outside Committee Member

Abstract

Copper is an essential cofactor of two mitochondrial enzymes: cytochrome c oxidase (COX) and the mitochondrial localized fraction of Cu-Zn superoxide dismutase (Sod1p). Copper incorporation into these enzymes is facilitated by a growing number of metallochaperone proteins. Here we describe two novel copper chaperones of COX, Cmc1 and Cmc2. In Saccharomyces cerevisiae, both Cmc1 and Cmc2 localize to the mitochondrial inner membrane facing the intermembrane space. Cmc1 and Cmc2 are essential for full expression of COX and cellular respiration, contain a twin Cx9C domain, and are conserved from yeast to humans. Additionally, the presence or absence of these proteins not only determines full assembly of functional COX but also affects metallation of Sod1 suggesting these proteins might play a role on co-modulation of copper transfer to COX and Sod1. CMC1 overexpression does not rescue the respiratory defect of cmc2 mutants or vise versa. However, Cmc2 physically interacts with Cmc1 and the absence of Cmc2 induces a 5-fold increase in Cmc1 accumulation in the mitochondrial membranes. We conclude that Cmc1 and Cmc2 have cooperative but non-overlapping functions in cytochrome c oxidase biogenesis.

Keywords

Copper; Cmc1; Cmc2 Mitochondria; Cytochrome C Oxidase; Superoxide Dismutase

Download

Share

COinS