Mitochondrial Gene Expression Landscape of S. Cerevisiae during Aging and Life Span Extension
2013 new Scholar Award in aging
Mitochondrial dysfunction is a hallmark of aging phenotypes and aging-related diseases, such as cancer, neurodegenerative diseases and cardiovascular disease. Healthy, functioning mitochondria require the coordinated expression of genes located on both the nuclear and mitochondrial genomes. Mitochondria have their own distinct gene expression machinery and the regulation mechanisms that govern mitochondrial gene expression are largely unknown. Importantly, it is becoming clear that the quantity and quality of mitochondrial gene expression is connected to aging phenotypes. Decades of groundbreaking research on nuclear-based gene expression do not provide sufficient insight into the mechanisms that guarantee the faithful expression of mitochondrial gene products. To close this gap in our understanding of mitochondrial biology, our goal is to directly observe all stages of mitochondrial gene expression and determine their regulatory mechanisms. We are proposing an approach that, through exploiting recent advances in modern molecular biology, will fully dissect mitochondrial gene expression. Recent technological advances in DNA sequencing allow whole genome analyses, bringing new insight into how nuclear gene expression is regulated. For the most part, these approaches have ignored the mitochondrial genome through either their experimental design or their computational analysis. We will adapt and apply a select set of quantitative genomic approaches to map the entire landscape of mitochondrial gene expression, querying across the mitochondrial genome, transcriptome, and mitochondrial-encoded proteome. In order to investigate how organismal aging disrupts the regulation of mitochondrial gene expression, we will apply our strategy to the budding yeast, Saccharomyces cerevisiae, where mitochondrial gene expression is best studied. Aged yeast cells exhibit similar characteristics of mitochondrial dysfunction in mammals including mitochondrial fragmentation, increased levels of mitochondrial reactive oxygen species, and increased loss of mitochondrial DNA in their progeny. By mapping mitochondrial gene expression through the yeast aging process, we will be able to pinpoint when and where the fidelity of mitochondrial gene expression is compromised.