Membrane Trafficking Pathways Mediate the Intracellular Distribution of Coenzyme Q

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

Coenzyme Q (CoQ) is essential for energy metabolism and also serves as an antioxidant that protects cell membranes from damage that accrues from life in the presence of oxygen. CoQ is insoluble in water, and its functions rely on its presence in the membrane. CoQ must be transported from the mitochondria where it is made, to other membranes throughout the cell. Cells are also able to take up CoQ from outside the cell and transport it to membranes within the cell. Such movement of CoQ restores energy production and antioxidant protection to cells. However, the mechanisms responsible for such CoQ movement remain mysterious. In this project investigators have identified three proteins that play crucial roles in CoQ movement to where it is needed. One of these proteins binds tightly to CoQ to help it move, and this project will identify how this CoQ “chaperone” protein works with other proteins in the cell components to enable CoQ function. The investigators will also characterize two other proteins they discovered that are essential for correct movement of CoQ. Elucidating the functional roles of these three proteins will advance our understanding of how CoQ is transported throughout the cell. This project will also train graduate and undergraduate students as researchers. Graduate students will teach and mentor undergraduate students, who are active participants in the scientific discoveries. Students will appreciate that there are many unsolved problems in membrane formation and movement within the cell, including routes yet to be discovered. Students will present their research findings at local conferences and at national and international meetings. Coenzyme Q (CoQ) is a hydrophobic lipid molecule essential for mitochondrial respiratory energy metabolism. It also serves as a vital antioxidant that protects cellular membranes from lipid peroxidation. CoQ is synthesized within the inner mitochondrial membrane and must be trafficked to non-mitochondrial membranes. CoQ-deficient cells supplemented with exogenously supplied CoQ are able to take up this insoluble lipid and transport it from the plasma membrane to the mitochondrial inner membrane, where it restores the function of respiratory electron transport. However, the pathways that mediate the intracellular distribution of CoQ remain poorly understood. In order to advance our understanding of CoQ trafficking, this project will characterize three proteins essential for the intracellular distribution of CoQ in the yeast Saccharomyces cerevisiae. The investigators will determine the structure of Coq10, a CoQ-binding protein conserved from yeast to humans. A mixed-vesicle fluorescence-based assay that detects movement of CoQ between vesicles will be used to assess the activity of the Coq10 polypeptide as a CoQ transporter. The project also aims to determine the function of conserved catalytic residues in Coq11. Evidence suggests that Coq11 modulates the mitochondrial CoQ pool and hence, its intracellular distribution. The investigators also discovered that Vps1 is required to mediate CoQ transport. A panel of vps1 mutants with defects in specific functions that affect membrane fusion, fission, and endomembrane trafficking will be used to identify the functional role(s) of Vps1 important for CoQ transport. This project will advance our understanding of how CoQ, and other hydrophobic molecules, are transported throughout cells. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.