What are the molecular mediators of neuronal mitophagy?
One of the major mechanisms utilized by cells to remove aged and/or damaged mitochondria is the selective removal of the organelle via autophagy, better known as mitophagy. Much research in the past decade examining mitophagy has been performed in transformed cultured cell lines, and has yielded the general cascade of events that occur in the mitophagic process (see illustration below). With modern genetic tools and recent discoveries, we are now in a place to systematically dissect the molecular mechanisms regulating mitophagy in neurons in vivo. We are taking a two step approach in: 1) identifying candidate genes involved in mitophagy in neurons, and their contribution to the mitophagic process; and 2) understanding the physiological consequences of disrupting neuronal mitophagy. Many of the candidate genes we will be testing are associated with neurodegenerative diseases when mutated in humans.
How does the local environment respond to mitophagy disruption in neurons?
Mitochondria, particularly damaged mitochondria, can be the source of various cellular threats including damaging reactive oxygen species (ROS). However, strict mitochondrial quality control is thought to act to keep a lid on these potentially damaging threats. Mitophagy and other forms of mitochondrial quality control have been strongly associated with the pathology of multiple neurodegenerative diseases, and we seek to understand more about the tissue and organismal level response to defective mitochondrial quality control in neurons. We are interested in understanding how supportive glial cells react to disrupted mitochondrial quality control in neurons, and how they can potentially aid (or harm) long-term neuronal function. The genetic tools we have developed in in Drosophila allow us to independently and simultaneously manipulate gene expression (Gal4/UAS and QF/QUAS system, see illustration below) in neurons and glia to test our hypotheses.
Mitochondria share characteristics with bacteria due to their evolutionary origin. While generally thought of as an "immune privileged" tissue, sterile inflammation in the nervous system has recently been demonstrated to be a contributing factor to neurodegenerative disease. We are interested in testing the hypothesis that disrupted mitophagy, and the consequences of damaged mitochondria not being efficiently degraded, can trigger a maladaptive immune response in neurons. We will test this idea on the cellular and physiological level.
How do disruptions in mitophagy contribute to other diseases?
We are interested in the process of mitophagy in biological contexts associated with disease. Disruptions to mitophagy have been linked to many other diseases, and we are interested to dig deeper into the cell biological and physiological defects associated with these diseases. We plan to model such mitophagy-associated diseases in the fly, cultured cells, and rodents.