The Involvement of Copper in Leigh Syndrome

Abstract

Leigh Syndrome is a neurodegenerative disease that presents with bilateral lesions in the brain. This condition is characterized by progressive loss of mental and movement abilities in which these symptoms start as early as three months old and usually results in death within two to three years. One major cause of Leigh syndrome is a mutation in the SURF1 gene. The loss of SURF1 causes a defect in cytochrome c oxidase (COX) assembly. Cytochrome c oxidase is required for the electron transport chain in cellular respiration. COX is the terminal electron accepting enzyme that requires more than 25 factors to assemble the subunits of this enzyme, including components to coordinate the early stages of mitochondrial translation and cofactor insertion such as MITRAC. For function COX requires several metals including copper. Copper is an essential element that is required for the proper functioning of mammalian cells. It is required for iron uptake, oxidative stress prevention, and the electron transport chain. Copper is especially important in mitochondria for COX, SOD, and storage in the matrix. Although copper is essential, maintaining a suitable balance of copper is important to prevent toxicity in the cell that causes dysfunctions and diseases to occur. There are many different measures in place to keep copper balanced, the details of how, what, who, and how many players involved are not completely understood. Much is known on the pathway of copper getting into the cell, into mitochondria to be distributed to enzymes, and through the mitochondrial carrier family protein (SLC25A3) into the matrix, but it is unknown how copper is exported out of the matrix. In this dissertation I investigated a potential role for copper in Leigh Syndrome and potential role for SURF1 in regulating copper availability in mitochondria. Understanding of this pathway could lead to much needed therapies to combat this disease and prevent infant death.