Protein aggregation and mitochondrial dysfunction are key factors in aging and in neurodegenerative disease,
like Alzheimer’s disease. It is clear that full understanding of mechanisms that neurons employ to combat these
toxic threats will be critical for development of clinical neuroprotective strategies.
The Driscoll lab has found that C. elegans neurons can sort and throw out neuronal debris for remote
degradation in a novel “extracellular garbage elimination” strategy. We call such extrusions, which are large
~.4um membrane-surrounded vesicles that can include protein aggregates and mitochondria, “exophers”. We
speculate that trash expulsion complements known intracellular protein and organelle degradation pathways to
help maintain homeostasis. Consistent with this idea, neurons that extrude aggregate-filled exophers maintain
better functionality than neurons that did not produce exophers. We also speculate that the mechanism of
aggregate/mitochondrial hand-off to neighboring cells might constitute a conserved process relevant to the
spread of pathological materials in mammalian neurodegenerative disease. Advancing understanding of the
newly discovered exopher biology is thus likely to be of high impact in the neuroscience field.
My interests is focused on deciphering why and how mitochondria are selected for expulsion in exophers. Data
suggest that dysfunctional mitochondria may be preferentially extruded, but understanding of the conditions for
segregation of particular mitochondria into the exopher compartment, and the cellular machinery that mediates
this distinction is in its infancy. I will utilize the powerful molecular genetic tools of C. elegans to investigate
principal mechanisms that mark, move, and expel mitochondria within exophers.
My first aim is to define conditions that induce production of mitochondrial exophers and verify that
mitochondria are of poor health under such conditions. I will use genetic means to test a range of
mitochondrially-focused damage (heteroplasmy, cristae disruption, quality control impairment) to reveal the
types of mitochondrial dysfunction that provoke extrusion for remote degradation. I will also investigate the
details by which mitochondrial superoxide elevation increases the production of mito-exophers using genetics,
optogenetics tools, mitochondrial assessment tools and high resolution microscopy.
My second aim is to identify genes that are required for mitochondrial exopher production. I will use
RNAi approaches to test candidate gene sets (including some uniquely available to us based on proteomics of
candidate mammalian mitochondrial-loaded exophers). Time permitting, I will also participate in an unbiased
screen for genes that can modulate production of exophers. I will initiate a detailed mechanistic study of 1-2
conserved genes to contribute some of the first molecular understanding of the exopher-genesis pathway.
Given the profound importance of mitochondria in all of biology, especially in neurodegenerative disease and
aging, the work I plan should be significant in carving out a new research area highly relevant to human health.