Grants and Contributions:

Grant or Award spanning more than one fiscal year (2017-2018 to 2018-2019).

Mitochondria are sub-cellular compartments responsible for producing the bulk of the energy our cells need for survival. In addition to their central role in energy production, mitochondria are crucial for programmed cell death, an important component of the life-death balance for every living cell. My lab is focusing on cytochrome oxidase (COX), the terminal electron acceptor of the mitochondrial respiratory chain, the energy-producing machinery. In addition to its protein subunits, COX also requires a host of accessory proteins that provide copper and heme A for enzyme assembly. In the most recent granting period, we have found that Cox17 is more abundant in wild-type stationary phase yeast and that loss of Cox17 results in an inability to induce apoptosis in stationary phase yeast, suggesting for the first time that this small protein, better known as a mitochondrial copper chaperone, may also have role in cellular quality control. In addition, we have found that a lack of assembled COX also leads to an increase in oxidative stress.

In the coming granting period, we will continue using the yeast, Saccharomyces cerevisiae, as a model for studying the consequences of a COX assembly defect in both the mitochondrial and broader cell context. Yeast has proven to be an excellent model for better understanding how mitochondria are formed and function, with direct application to our understanding of human diseases that involve dysfunctional mitochondria, such as neurodegeneration and cancers. Our use of stationary phase yeast, which have ceased growing and dividing, is particularly relevant to understanding the consequences of mitochondrial defects in diseases involving human tissues that have ceased growing and dividing, such as neurons. Using standard approaches in yeast molecular cell biology and biochemistry and taking advantage of our large mutant collection, we will determine how Cox17 acts in the induction of apoptosis and what other molecules are involved in this novel function for Cox17. We will also determine the molecular basis for the increased abundance of Cox17 at stationary phase and how a loss of COX assembly leads to changes in the amount of protein and enzymatic activity of the Cu,Zn-superoxide dismutase in stationary phase yeast.

The proposed experiments are the continuation of the long-standing NSERC-funded program in my lab and will improve our understanding of the cellular consequences of COX assembly defects, as well as having direct relevance to our understanding of the molecular bases for inherited human COX deficiencies. This work will also have implications for our understanding of the etiologies and pathophysiology underlying neurodegenerative diseases and cancer, given that stationary phase yeast are an appropriate model for the terminally differentiated tissues typically involved in these human diseases.