Deconstructing a novel pathway of mitochondrial-driven inflammation

Cells die in our bodies all the time, when in check, this is a good thing, cell death eliminates damaged or useless cells. However, too much or too little cell death is associated with many diseases including neurodegeneration and cancer. Key to cell death are tiny organelles called mitochondria - these are present in all our cells.

As cells start to die, mitochondria become leaky, releasing proteins that cause the cell to commit suicide. Recently, various labs have found that as mitochondria become leaky they also cause inflammation. This type of inflammation has important roles in how we fight infection, cancer and how we age.

Nonetheless, how mitochondria cause these effects is unknown. Investigating this question, we found that leaky mitochondria get coated in a protein called ubiquitin that signals inflammation. This is an exciting finding, however there are many big questions remaining that our project aims to address.

Firstly, we want to understand why ubiquitin gets onto mitochondria, essentially asking what is the machinery in the cell that puts ubiquitin on the mitochondria. For this, we will combine targeted ideas alongside new methods called genome-editing based screens.

Secondly, we will ask why leaky mitochondria cause inflammation. We will investigate various possibilities such as examining the similarities between leaky mitochondria and intracellular bacteria.

Finally, we want to understand the importance of this pathway in key biological processes. For this purpose, we will develop methods to remove ubiquitin from mitochondria, thus removing the inflammatory signal. Using this method, we will ask whether we can block the inflammatory effects of dying and old cells.

In sum, our project will provide exciting new insight into how cells trigger inflammation upon a cell death stress. We hope that this will also provide new ways to think about therapeutic targeting inflammation in diseases including, but not limited to, aging and cancer.