Gerald S Shadel, PhD

In humans, as in most animal cells, genetic information is housed not only in the nucleus, but also in mitochondria. Mitochondrial DNA (mtDNA) encodes thirteen essential proteins of the oxidative phosphorylation complexes as well as 22 tRNAs and 2 rRNAs required to translate these thirteen mRNAs in the mitochondrial matrix. Mutations in mtDNA cause maternally inherited neuromuscular disorders due to declines in cellular energy metabolism. In addition, mtDNA mutations accumulate in normal aging tissues, certain tumors, and have been implicated in late-onset diseases such a Alzheimer's, Parkinson's, and diabetes, indicating that the pathology of dysfunctional mitochondria is only beginning to be unraveled. The research in my laboratory is directed toward understanding the mechanism of gene expression in human mitochondria and its impact on human aging and disease. The ultimate goal is to understand the full impact of dysfunctional mitochondrial gene expression on human health and use this information to design specific interventions to treat mitochondria-based disease and age-related pathology Specifically, we focus on nucleus-encoded factors that are imported into the organelle to regulate transcription, translation, replication, and maintenance of mtDNA. We are also concerned with signaling pathways that connect the nuclear and mitochondrial genomes to coordinate gene expession patterns in both compartments. We use multiple approaches to this problem including the employment of mouse and yeast (S. cerevisiae) genetic model systems, biochemical characterization of mitochondrial transcription events and interactions, and in vivo approaches in cultured mammalian cells.

Major Ongoing Projects:

1. Regulation of mitochondrial gene expression in vivo and in vitro.

2. Signaling pathways that regulate mitochondrial function and respond to mitochondrial dysfunction in human disease and aging.

3. Mitochondrial dysfunction and oxidative stress in Ataxia-Telangiectasia.

4. Role of the Target of Rapamycin (TOR) pathway and reactive oxygen species (ROS) in regulating mitochondrial function and longevity.

5. Role of mtDNA instability and mitochondrial reactive oxygen species (ROS) in cancer.

6. Mitochondria in antiviral signaling and immune system function