Function and maintenance of mitochondria depend on their constant dynamic fission and fusion. Dysregulation of mitochondrial dynamics is associated with dysregulation of organelle function and quality control, which is associated with cell death and neurodegeneration. As such, membrane remodeling proteins are critical to sustain proper mitochondrial function, and cell health. We investigate how macromolecular protein complexes coordinate critical mitochondrial membrane events that control cell death/survival mechanisms involved in neurodegeneration. We are currently focused on two outstanding questions:
1. How does remodeling of mitochondrial membranes control cell death/survival?
BAR proteins mediate membrane tubulation and are primarily associated with formation of constricted necks of clathrin-coated pits during endocytosis. Knockdown of BAR protein endophilin B1 leads to impaired mitochondrial function, inhibition of Bax-dependent cell death, and dysregulation of autophagy, among other things. The role of endophilin B1 at the mitochondria is enigmatic, but suggests that BAR proteins do much more than tubulate membranes. Exactly how endophilin B1 interacts with mitochondrial membranes and how its remodeling activity is regulated by membrane lipids and accessory proteins, remains poorly understood.
2. What role does amyloid protein mis-folding play in the regulation of mitochondrial membrane remodeling and cell death?
Mutant forms of Huntingtin protein (mtHtt) causes Huntington’s disease, although, the mechanisms by which mtHtt elicits neurodegeneration remains a mystery. Htt exhibits anti-apoptotic properties, and is known to interact with both dynamin and endophilin, suggesting it may play a role in mitochondrial dynamics.
Our methods include molecular biology, protein expression and purification (using bacterial, insect and mammalian expression systems), protein characterization- and protein-lipid interaction assays (SPR, ITC, gel filtration chromatography, etc.), and cryo-electron microscopy. The goal of our research is to reveal how the interplay between membranes and proteins coordinate critical intracellular events that control cell death/survival, and to describe how these processes play a role in neurodegeneration. Our long-term objective is to identify novel potential drug targets for prevention and treatment of neurodegenerative diseases, like Huntington’s.