Mitochondrial number is very tightly regulated within the cell. Developing an understanding of regulation of mitochondrial number and metabolism is important in almost every area of human health and disease. The goal of this proposal is to investigate the phenomenon of nuclear/mitochondrial communication and its role in regulation of mitochondrial number. The working hypothesis is that mitochondria have evolved pathways very similar to the quorum sensing pathways of their bacterial ancestors to communicate the need to increase or decrease mitochondrial content in the cell. Three criteria will used to determine if a quorum sensing type signaling pathway has been conserved in mitochondria. The first is the presence of a quorum sensing-like signaling molecule produced and released from the mitochondria. This molecule will be detected using methods similar to those established for isolating quorum sensing molecules in bacteria. The second criterion is the ability of mitochondrially derived molecules to drive transcription of mitochondrial biogenesis related molecules. The third criterion is the ability of the mitochondrially derived molecules to cause or suppress mitochondrial biogenesis in a whole cell system. The finding that mitochondria contain a pathway similar to bacterial quorum sensing would allow a more complete understanding of the regulation of mitochondrial number and metabolism in the cell, and could ultimately lead to better understanding of a multitude of human conditions where mitochondrial number is important, including but not limited to cancer, aging, mitochondrial DNA based disease, diabetes, and obesity. In addition, the identification of a lipid based signal for mitochondrial biogenesis would open the door for pharmacological intervention in these diseases.
Dysregulation of mitochondrial metabolism leads to decreased energy production, increased reactive oxygen species (ROS), and altered apoptosis. These three factors play a role in a multitude of diseases, including heart disease, diabetes, cancer, obesity, and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The goal of this project is to investigate the way in which cells regulate the amount of mitochondria within a cell, with an eye towards their evolutionary origins.
|Clay, Hayley B; Parl, Angelika K; Mitchell, Sabrina L et al. (2016) Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling. PLoS One 11:e0151171|
|Parl, Angelika; Mitchell, Sabrina L; Clay, Hayley B et al. (2013) The mitochondrial fatty acid synthesis (mtFASII) pathway is capable of mediating nuclear-mitochondrial cross talk through the PPAR system of transcriptional activation. Biochem Biophys Res Commun 441:418-24|