Thomas Melia PhD
Associate Professor of Cell Biology
Exploring how a cell consumes itself -- Macroautophagy is classically defined as a pathway for the nonspecific sequestration and degradation of cytosolic material when the cell is faced with persistent starvation. This cytosolic material is captured within a double-membraned vesicle (the autophagosome) which forms de novo and ultimately traffics the material to the lysosome for degradation (and release of valuable nutrients). However, this pathway can also be utilized as a stress response to a wide variety of specific cellular insults. The ability to capture and degrade specific cytoplasmic targets including protein aggregates, invading pathogens or even whole dysfunctional organelles forms the basis of the cell’s response to diseases ranging from neurodegeneration to cancer and heart disease. In each case, large cytoplasmic targets are identified and encapsulated newly-formed autophagosomes for delivery to the lysosome. How these targets are identified and how this organelle forms are the major foci of our laboratory.
Extensive Research Description
Faced with persistent starvation, the cell can “consume itself”. Macroautophagy is a pathway for the sequestration and ultimate delivery of cytosol to the lysosome for degradation and release of valuable nutrients. Interestingly, the same pathway can be highjacked to selectively dispose of cytosolic toxins ranging from protein inclusions to dying organelles, and thus macroautophagy has been linked to a range of diseases (neurodegeneration, heart disease, cancer, viral infection, etc.). However, despite this widespread translational interest, fundamental questions remain unanswered.
We are studying how the cell forms, de novo, a new organelle (the autophagosome) to sequester free cytosol. In particular, we are interested in what membranes are harvested for this purpose, how the autophagosome grows, how cargo is targeted to these membranes and how the cell carries out potentially complex membrane dynamics and intracellular fusion to effect the formation of the unique double-membrane structure of the autophagosome. Ultimately we expect that protein function and membrane architecture will be revealed by combining low resolution cell-based assays with high resolution imaging (electron cryo-microscopy) of both isolated organelles and reconstituted autophagosome mimetics, vesicles imbued with all the detail we currently possess about autophagosome proteomic character.