Mitochondria play a very important role in many aspects of cellular biology and mitochondrial dysfunction contributes to most age--?related human diseases. As expected, there are a number of systems dedicated to maintaining mitochondrial function under stress. We recently identified an AAA ATPase that is required for the normal extraction of proteins that mislocalize to mitochondria, specifically those that have a single C--?terminal transmembrane domain (tail--?anchored). When this protein, named Msp1 in yeast and ATAD1 in mammals, is absent, cells exhibit progressive loss of mitochondrial respiratory function. The goals of this project are to: 1) define the mechanisms of substrate recognition and extraction using the yeast system; 2) determine whether ATAD1 is required for the maintenance of mitochondrial function in the mouse heart; 3) examine the impact of mitochondrial function on a patient with aberrant tail--?anchored protein expression and a progressive neurodegenerative disease; 4) use Msp1/ATAD1 as a model protein by which to interrogate the mechanisms and importance of mitochondria--?to--?peroxisome vesicular trafficking; and 5) examine the role of Msp1/ATAD1 in limiting mitochondrial localization of peroxisomal proteins in conditions of impaired peroxisomal biogenesis, such as Zellweger syndrome.
We have discovered that the yeast Msp1 and mammalian ATAD1 proteins perform a function that is important for the maintenance of the integrity of mitochondria, which are required for the production of utilizable energy in most tissues, particularly the heart. We propose to define the mechanisms underlying this function and assess its importance in animal models and in cellular models of human disease. We also propose to determine the role of these proteins in peroxisome biogenesis.
|Van Vranken, Jonathan G; Rutter, Jared (2016) The Whole (Cell) Is Less Than the Sum of Its Parts. Cell 166:1078-1079|