Mitochondria are intracellular organelles that are essential for many cellular functions that regulate cell survival and cell death. Thus, dysregulation of mitochondria may lead to cell death and disease. Death of neurons (neurodegeneration) contributes to the development of devastating ailments, such as Huntington’s disease, a hereditary progressively deteriorating condition characterized by uncoordinated and involuntary movement and dementia, with no known cure.

Mitochondrial function is maintained by dynamic fission and fusion events, opposing processes of mitochondria dividing (fission) and joining together into larger structures (fusion). This constant cycle is controlled by various different proteins that specifically bind to mitochondrial membranes to modify their shapes. Exactly how these proteins control mitochondrial behaviour is not fully understood. Our lab studies how these proteins interact with mitochondrial membranes to promote fission and fusion using a variety of various methods, including cryo-electron microscopy. Cryo-electron microscopy has the power to reveal very detailed information of molecules, like proteins or protein-lipid complexes. We use this technique and others to reveal in great detail the organization of proteins that modulate mitochondrial membrane shape to increase our understanding of cellular events that lead to neuronal cell death or survival. Our goal is to describe novel cellular mechanisms and to identify potential molecular targets for drug development and prevention of catastrophic neurodegenerative diseases like Huntington’s disease.

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.