Thomas Melia, PhD

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.