Investigating the molecular mechanism and function of mitochondrial tethering

Project Summary We are interested in the dynamic interplay between the intracellular distribution of mitochondria and cellular function. Mitochondria are important not only for cellular energy production but also play critical roles in cell cycle progression, differentiation, immune responses, lipid and calcium homeostasis, and apoptotic cell death. These diverse roles are intimately connected to mitochondrial shape and cellular position. Thus, it is not surprising aberrant mitochondrial architecture has been implicated in an ever-increasing number of diseases. It is well appreciated that mitochondrial division, fusion, and motility all contribute to the overall distribution of mitochondria within a cell. However, the critical contributions of actively tethering the organelle to specific cellular sites and structures, including other organelles, are becoming increasingly evident. While tethering plays a critical role in mitochondrial positioning, interorganelle contact, and, consequently, cellular function in cells from yeast to neurons, the molecular mechanisms and regulation are poorly understood. In the aims of this grant, we will address this deficit by using a mitochondria-ER-cortex tether in yeast as a model to understand the mechanism and regulation of mitochondrial tethers and the multifunctional mitochondrial membrane contact sites they create. The proposed work will address the exciting and unexpected impacts mitochondrial tethers have on cellular organization and function. The goals are to uncover fundamental mechanisms used by mitochondrial tethers to position mitochondria and form interorganelle contacts and elucidate the functional and physiological consequences of these activities. In doing so, this work will provide insight into novel therapeutic strategies for a range of human disease conditions in which the manipulation of the position and the contacts made by mitochondria can be used to positively influence cellular health and homeostasis.